Is SMARCA4 p.Pro313Ala (c.937C>G) pathogenic?

SMARCA4 p.Pro313Ala (c.937C>G) is classified Uncertain significance in SMARCA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: ambiguous (0.3884); Very rare (popmax 0.00225%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Pro313Ala (c.937C>G)?

SMARCA4 p.Pro313Ala (c.937C>G) is associated with hereditary neoplastic syndrome, rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Pro313Ala (c.937C>G) in the general population?

SMARCA4 p.Pro313Ala (c.937C>G) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about SMARCA4 p.Pro313Ala (c.937C>G)?

AlphaMissense predicts ambiguous (score 0.3884) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro313Ala

c.937C>G · rs1195480403 · VCV1766733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3884	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -6.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,911 bp · p 0.24 · regional, not allelic
Overall
CADD	23.7	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 0.00225% East Asian · 1/44,370 alleles

Overall 6.24e-05% 1/1,602,552 alleles · very rare exomes 1/1,450,254 · genomes 0/152,298 · joint denominator

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: SMARCA4
Protein: p.Pro313Ala
Coding: c.937C>G
MANE Select: NM_003072
dbSNP: rs1195480403
Type: single nucleotide variant
Location: chr19:10987743 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 313: the 'disordered' region

Full SMARCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhabdoid tumor predisposition syndrome 2

Similar variants

SMARCA4 p.Pro313Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro313= Likely benign ★ same residue
SMARCA4 c.1943+1G>A Likely pathogenic ★★ same condition
SMARCA4 c.2274+1G>T Likely pathogenic ★★ same condition
SMARCA4 c.2438+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMARCA4 c.3216-1G>C Likely pathogenic ★★ same condition
SMARCA4 c.3216-2A>G Likely pathogenic ★★ same condition
SMARCA4 c.3546+1G>A Likely pathogenic ★★ 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/smarca4-p-pro313ala (accessed [today's date]).

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