Is SMARCA4 p.Ala433Pro (c.1297G>C) pathogenic?

SMARCA4 p.Ala433Pro (c.1297G>C) is classified Uncertain significance in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-23). AlphaMissense: likely pathogenic (0.997); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Ala433Pro (c.1297G>C)?

SMARCA4 p.Ala433Pro (c.1297G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SMARCA4 p.Ala433Pro (c.1297G>C) in the general population?

SMARCA4 p.Ala433Pro (c.1297G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMARCA4 p.Ala433Pro (c.1297G>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

SMARCA4 p.Ala433Pro

c.1297G>C · VCV4827323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic
REVEL	0.453	indeterminate
SaProt	LLR -13.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 5,618 bp · p 6.4e-18 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMARCA4
Protein: p.Ala433Pro
Coding: c.1297G>C
MANE Select: NM_003072
Type: single nucleotide variant
Location: chr19:10991201 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 433: an α-helix

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.Ala433= 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
SMARCA4 c.3952-1G>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-ala433pro (accessed [today's date]).

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