Is SMARCA4 p.Pro305= (c.915G>A) pathogenic?

SMARCA4 p.Pro305= (c.915G>A) is classified Benign in SMARCA4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Low-frequency (popmax 4.68%, afr); Associated with Coffin-Siris syndrome.

What condition is associated with SMARCA4 p.Pro305= (c.915G>A)?

SMARCA4 p.Pro305= (c.915G>A) is associated with Coffin-Siris syndrome, rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16 (ClinVar).

How common is SMARCA4 p.Pro305= (c.915G>A) in the general population?

SMARCA4 p.Pro305= (c.915G>A) is low-frequency (popmax 4.68%, afr) (gnomAD).

SMARCA4 p.Pro305=

c.915G>A · rs149573400 · VCV126366

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.68%, afr)

Conditions

Coffin-Siris syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -4.1
Overall
CADD	6.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.68% African / African-American · 3,503/74,790 alleles

Filtering AF 4.55% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.5%

Overall 0.245% 3,951/1,609,678 alleles · low-frequency exomes 1,988/1,457,760 · genomes 1,963/151,918 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.68%	21
Remaining individualsnot grpmax-eligible	0.299%	335
Admixed American	0.264%	379
Middle Eastern	0.182%	550
South Asian	0.00881%	11,355
European (non-Finnish)	0.00722%	13,857

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.Pro305=
Coding: c.915G>A
MANE Select: NM_003072
dbSNP: rs149573400
Type: single nucleotide variant
Location: chr19:10987721 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 305: the 'disordered' region

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

Disease context

Coffin-Siris syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: rhabdoid tumor predisposition syndrome 2 intellectual disability, autosomal dominant 16 hereditary neoplastic syndrome

Similar variants

SMARCA4 p.Pro305Arg Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro305Gln Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro305Leu Conflicting classifications of pathogenicity ★ ⚠ 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
SMARCA4 c.3216-2A>G 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-pro305 (accessed [today's date]).

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