Is SMARCA4 p.Pro57Arg (c.170C>G) pathogenic?

SMARCA4 p.Pro57Arg (c.170C>G) is classified Uncertain significance in SMARCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.4404); Very rare (popmax 8.5e-05%, nfe); Associated with rhabdoid tumor predisposition syndrome 2.

What condition is associated with SMARCA4 p.Pro57Arg (c.170C>G)?

SMARCA4 p.Pro57Arg (c.170C>G) is associated with rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Pro57Arg (c.170C>G) in the general population?

SMARCA4 p.Pro57Arg (c.170C>G) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

How is Rhabdoid tumor predisposition syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SMARCA4 p.Pro57Arg (c.170C>G)?

AlphaMissense predicts ambiguous (score 0.4404) — an in-silico prediction, not a clinical call.

SMARCA4 p.Pro57Arg

c.170C>G · rs1568417458 · VCV1044156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

rhabdoid tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4404	ambiguous
REVEL	0.375	indeterminate
SaProt	LLR -8.36	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.2, phastCons 0.76
Regional constraint	o/e 0.81	unconstrained · MANE · 2,200 bp · p 0.0027 · regional, not allelic
Overall
CADD	20.5	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 8.5e-05% European (non-Finnish) · 1/1,176,250 alleles

Overall 6.23e-05% 1/1,605,196 alleles · very rare exomes 1/1,452,856 · genomes 0/152,340 · 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.Pro57Arg
Coding: c.170C>G
MANE Select: NM_003072
dbSNP: rs1568417458
Type: single nucleotide variant
Location: chr19:10984321 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 57: the 'necessary for interaction with ss18l1/crest' region; the 'disordered' region

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

Disease context

rhabdoid tumor predisposition syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rhabdoid tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

SMARCA4 p.Pro57His Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro57Leu Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro57Ala Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro57= 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

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-pro57arg (accessed [today's date]).

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