Is SMARCA4 p.Arg451Pro (c.1352G>C) pathogenic?

SMARCA4 p.Arg451Pro (c.1352G>C) is classified Uncertain significance in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-20). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMARCA4 p.Arg451Pro (c.1352G>C)?

SMARCA4 p.Arg451Pro (c.1352G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SMARCA4 p.Arg451Pro (c.1352G>C) in the general population?

SMARCA4 p.Arg451Pro (c.1352G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMARCA4 p.Arg451Pro (c.1352G>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

SMARCA4 p.Arg451Pro

c.1352G>C · rs2086534991 · VCV985830

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 5% in SMARCA4
REVEL	0.652	pathogenic-leaning
SaProt	LLR -17.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	32.0	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.Arg451Pro
Coding: c.1352G>C
MANE Select: NM_003072
dbSNP: rs2086534991
Type: single nucleotide variant
Location: chr19:10991256 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 451: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCA4 p.Arg451Cys Pathogenic/Likely pathogenic ★★ same residue
SMARCA4 p.Arg451His Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Arg451Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SMARCA4 p.Arg451= Likely benign ★ same residue
SMARCA4 p.Arg885Cys Pathogenic/Likely pathogenic ★★ same condition
SMARCA4 p.Thr894Met Likely pathogenic ★ ⚠ same condition
SMARCA4 c.1943+1G>A Likely pathogenic ★★ same type
SMARCA4 c.2274+1G>T Likely pathogenic ★★ same type

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-arg451pro (accessed [today's date]).

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