Is SMARCA4 p.Ser312Phe (c.935C>T) pathogenic?

SMARCA4 p.Ser312Phe (c.935C>T) is classified Uncertain significance in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-01). AlphaMissense: likely pathogenic (0.908); Very rare (popmax 0.000125%); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Ser312Phe (c.935C>T)?

SMARCA4 p.Ser312Phe (c.935C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Ser312Phe (c.935C>T) in the general population?

SMARCA4 p.Ser312Phe (c.935C>T) is very rare (popmax 0.000125%) (gnomAD).

What do computational predictors say about SMARCA4 p.Ser312Phe (c.935C>T)?

AlphaMissense predicts likely pathogenic (score 0.908) — an in-silico prediction, not a clinical call.

SMARCA4 p.Ser312Phe

c.935C>T · rs767826277 · VCV1766675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000125%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.908	likely pathogenic
REVEL	0.525	indeterminate
SaProt	LLR -9.89	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	24.7	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 0.000125%

Overall 0.000125% 2/1,600,354 alleles · very rare exomes 2/1,448,056 · 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.Ser312Phe
Coding: c.935C>T
MANE Select: NM_003072
dbSNP: rs767826277
Type: single nucleotide variant
Location: chr19:10987741 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 312: 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

Similar variants

SMARCA4 p.Ser312Tyr Uncertain significance ★ ⚠ same residue
SMARCA4 p.Ser312= Likely benign ★ same residue
SMARCA4 c.1943+1G>A 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.3546+1G>A Likely pathogenic ★★ same condition
SMARCA4 c.3774+2T>A Likely pathogenic ★★ same condition
SMARCA4 c.3951+2T>C 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-ser312phe (accessed [today's date]).

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