Is SAMD9 p.Trp752Arg (c.2254T>A) pathogenic?

SAMD9 p.Trp752Arg (c.2254T>A) is classified Conflicting classifications of pathogenicity in SAMD9 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-11). AlphaMissense: likely pathogenic (0.9827); Ultra-rare (popmax 0.0212%, nfe); Associated with monosomy 7 myelodysplasia and leukemia syndrome 2.

What condition is associated with SAMD9 p.Trp752Arg (c.2254T>A)?

SAMD9 p.Trp752Arg (c.2254T>A) is associated with monosomy 7 myelodysplasia and leukemia syndrome 2 (ClinVar).

How common is SAMD9 p.Trp752Arg (c.2254T>A) in the general population?

SAMD9 p.Trp752Arg (c.2254T>A) is ultra-rare (popmax 0.0212%, nfe) (gnomAD).

What do computational predictors say about SAMD9 p.Trp752Arg (c.2254T>A)?

AlphaMissense predicts likely pathogenic (score 0.9827) — an in-silico prediction, not a clinical call.

SAMD9 p.Trp752Arg

c.2254T>A · rs148339415 · VCV1422840

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monosomy 7 myelodysplasia and leukemia syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9827	likely pathogenic · top 1% in SAMD9
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 1,217 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	24.1	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 0.0212% European (non-Finnish) · 250/1,179,890 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0159% 257/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0212%	4,720
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00333%	30,003

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: SAMD9
Protein: p.Trp752Arg
Coding: c.2254T>A
MANE Select: NM_017654
dbSNP: rs148339415
Type: single nucleotide variant
Location: chr7:93103844 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB

Full SAMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

monosomy 7 myelodysplasia and leukemia syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial monosomy 7 syndrome (Orphanet):

Onset: Childhood, Infancy

Similar variants

SAMD9 p.Trp752Cys Uncertain significance ★★ ⚠ same residue
SAMD9 p.Trp752Ter Uncertain significance ★ same residue
SAMD9 p.Arg982Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
SAMD9 p.Leu1511Ser Likely pathogenic ★★ ⚠ same condition
SAMD9 p.Ala1087Val Uncertain significance ★★ ⚠ same condition
SAMD9 p.Ala1457Val Uncertain significance ★★ ⚠ same condition
SAMD9 p.Arg1040Gly Uncertain significance ★★ ⚠ same condition
SAMD9 p.Arg1334Ile 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/samd9-p-trp752arg (accessed [today's date]).

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