- Class
- Soluble (p=0.92), non-enzyme (p=1.00); a large immune / signalling effector — an antiviral, growth-restricting multidomain protein.
- Disease Map
- Three Mendelian diseases, mapped. Gain-of-function variants at 880 (ataxia-pancytopenia / monosomy-7 MDS) and 626 (SCA49) fall within the predicted effector core.
- Effector Pocket
- High-confidence pocket (0.89). A residue-level site in the central effector core — a candidate ligand / interaction site on a 1,584-residue protein.
- Architecture
- N-terminal SAM domain (14–79); a large, predominantly ordered (~6% disorder) multidomain effector core (STAND / NTPase-like → TPR → OB).
- Clean Signal
- No membrane or amyloid signal.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
SAMD9L carries an outsized clinical burden for a protein no one has drugged. Germline gain-of-function variants cause a spectrum of severe inherited disease: ataxia-pancytopenia syndrome, myelodysplasia with monosomy 7 / bone-marrow-failure predisposition, and spinocerebellar ataxia 49 (SCA49). It is a large, antiviral, growth-restricting multidomain effector whose molecular mechanism is still being worked out. And it is enormous — 1,584 residues — which is exactly why it is hard to reason about.
Crucially, no experimental structure is available in the public PDB as of mid-2026 (the first cryo-EM structures of human SAMD9L were reported in a 2026 preprint, but the coordinates are not yet released). It remains understudied (IDG Tbio). So the practical problem is the same as for any dark giant: where are the domains, where do the disease variants act, and is there a targetable site? Everything below is computed from the canonical 1,584-residue sequence and derived structural predictions, with no experimental SAMD9L structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| SAM domain | 14–79 | N-terminal protein-interaction module; a clean, small unit to express and assay first. |
| Effector core | ~150–1400 | Large multidomain effector core (STAND / NTPase-like → TPR → OB); ~6% disorder overall. Carries the gain-of-function disease variants (626 SCA49; 880, 986 ataxia-pancytopenia / monosomy-7 MDS) and the predicted pocket. |
The Predicted Pocket
The Predicted Effector-Core Pocket
A high-confidence pocket (0.89) in the central effector core (residues 687–990) — the region that also contains the gain-of-function disease variants. That gives a first, concrete hypothesis for where to intervene on a protein otherwise too large to reason about by eye. No known binder.
Site: Central effector core, residues 687–990
Post-Translational & Structural Features
Specific, Testable Residues
- Predominantly ordered (~6% disorder). Despite its size, most of SAMD9L is foldable — so domain-by-domain expression is realistic.
- N-terminal SAM domain (14–79). A protein-interaction module; a clean, small unit to express and assay first.
- No membrane or amyloid signal. A soluble effector; the biology is intracellular.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| Effector-core pocket (687–990) | Fragment / ligand screen at the pocket | A chemical starting point on the core |
| Variants act in the effector core | Growth-restriction assay: 626 / 880 vs WT | Structural mechanism of gain-of-function |
| Domain map (SAM + core) | Domain-by-domain expression | Which domains fold independently |
| Immune / growth-restricting role | Antiviral / proliferation assays ± variants | Function of the core and its pocket |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a substitute for a structure or an assay. No result here has been validated in the wet lab.
- Structures are imminent. No SAMD9L coordinates are in the public PDB today, but the first cryo-EM structures have been reported in a 2026 preprint (release pending). This profile is the functional / variant annotation, which a set of coordinates does not by itself provide.
- Paralog caution. SAMD9L's paralog SAMD9 already has experimental structures (e.g. a DNA-binding-domain entry) — these are a different gene and must not be read as SAMD9L structures.
All predictions were generated with Orbion's Astra suite from the canonical SAMD9L sequence (UniProt Q8IVG5), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q8IVG5 (SAMD9L, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. SAMD9L target record — Tbio. pharos.nih.gov.
- [3]Chen D.-H., Below J.E., Shimamura A., et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am. J. Hum. Genet. 98(6), 1146–1158 (2016). https://doi.org/10.1016/j.ajhg.2016.04.009
- [4]Tesi B., Davidsson J., Voss M., et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms. Blood 129(16), 2266–2279 (2017). https://doi.org/10.1182/blood-2016-10-743302
- [5]Corral-Juan M., Serrano-Munuera C., Rábano A., et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 4(2), fcac030 (2022). https://doi.org/10.1093/braincomms/fcac030
- [6]Peng S., Meng X., Zhang F., et al. Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L. Proc. Natl. Acad. Sci. USA 119(4), e2116550119 (2022). https://doi.org/10.1073/pnas.2116550119