Is SAMD9L p.Arg285Trp (c.853C>T) pathogenic?

SAMD9L p.Arg285Trp (c.853C>T) is classified Conflicting classifications of pathogenicity in SAMD9L (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-24). AlphaMissense: ambiguous (0.3501); Ultra-rare (popmax 0.0691%, eas); Associated with monosomy 7 myelodysplasia and leukemia syndrome 1.

What condition is associated with SAMD9L p.Arg285Trp (c.853C>T)?

SAMD9L p.Arg285Trp (c.853C>T) is associated with monosomy 7 myelodysplasia and leukemia syndrome 1, ataxia-pancytopenia syndrome, spinocerebellar ataxia 49 (ClinVar).

How common is SAMD9L p.Arg285Trp (c.853C>T) in the general population?

SAMD9L p.Arg285Trp (c.853C>T) is ultra-rare (popmax 0.0691%, eas) (gnomAD).

What do computational predictors say about SAMD9L p.Arg285Trp (c.853C>T)?

AlphaMissense predicts ambiguous (score 0.3501) — an in-silico prediction, not a clinical call.

SAMD9L p.Arg285Trp

c.853C>T · rs746980471 · VCV1922426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3501 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

monosomy 7 myelodysplasia and leukemia syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3501	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -10.80	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 921 bp · p 0.59 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0691% East Asian · 31/44,890 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0434%

Overall 0.00279% 45/1,612,162 alleles · ultra-rare exomes 44/1,460,154 · genomes 1/152,008 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0691%	1,448
Finnishnot grpmax-eligible	0.00481%	20,804
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,468
South Asian	0.0011%	91,072
European (non-Finnish)	0.000678%	147,487

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SAMD9L
Protein: p.Arg285Trp
Coding: c.853C>T
MANE Select: NM_152703
dbSNP: rs746980471
Type: single nucleotide variant
Location: chr7:93135119 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.85

Full SAMD9L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

monosomy 7 myelodysplasia and leukemia syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ataxia-pancytopenia syndrome spinocerebellar ataxia 49

For Familial monosomy 7 syndrome (Orphanet):

Onset: Childhood, Infancy

Similar variants

SAMD9L p.Arg285Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
SAMD9L p.Arg285Leu Uncertain significance ★ ⚠ same residue
SAMD9L p.Arg986Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
SAMD9L p.His880Gln Pathogenic ★★ ⚠ same condition
SAMD9L p.Ala1087Val Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala1156Glu Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala354Val Uncertain significance ★★ ⚠ same condition
SAMD9L p.Ala442Pro Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/samd9l-p-arg285trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown