Is SMARCA4 p.Pro197= (c.591C>A) pathogenic?

SMARCA4 p.Pro197= (c.591C>A) is classified Likely benign in SMARCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-16). Very rare (popmax 0.000775%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Pro197= (c.591C>A)?

SMARCA4 p.Pro197= (c.591C>A) is associated with hereditary neoplastic syndrome, rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Pro197= (c.591C>A) in the general population?

SMARCA4 p.Pro197= (c.591C>A) is very rare (popmax 0.000775%, nfe) (gnomAD).

SMARCA4 p.Pro197=

c.591C>A · rs572753619 · VCV415073

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000775%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -4.1
Overall
CADD	0.309	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000775% European (non-Finnish) · 9/1,161,244 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000264%

Overall 0.000571% 9/1,575,496 alleles · very rare exomes 7/1,423,264 · genomes 2/152,232 · 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.Pro197=
Coding: c.591C>A
MANE Select: NM_003072
dbSNP: rs572753619
Type: single nucleotide variant
Location: chr19:10986424 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 197: the qlq domain; the 'necessary for interaction with ss18l1/crest' region; 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

Also linked: rhabdoid tumor predisposition syndrome 2

Similar variants

SMARCA4 p.Pro197Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro197Ser Benign/Likely benign ★★ same residue
SMARCA4 p.Pro197Thr Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro197_Leu200del Uncertain significance ★ 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-pro197 (accessed [today's date]).

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