Is SMARCA4 p.Pro358= (c.1074G>A) pathogenic?

SMARCA4 p.Pro358= (c.1074G>A) is classified Benign/Likely benign in SMARCA4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0161%, nfe); Associated with Coffin-Siris syndrome.

What condition is associated with SMARCA4 p.Pro358= (c.1074G>A)?

SMARCA4 p.Pro358= (c.1074G>A) is associated with Coffin-Siris syndrome, rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16 (ClinVar).

How common is SMARCA4 p.Pro358= (c.1074G>A) in the general population?

SMARCA4 p.Pro358= (c.1074G>A) is ultra-rare (popmax 0.0161%, nfe) (gnomAD).

SMARCA4 p.Pro358=

c.1074G>A · rs374167170 · VCV238358

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, nfe)

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 -11	GERP -4.4
Overall
CADD	2.342	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0161% European (non-Finnish) · 190/1,179,938 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0121% 195/1,612,926 alleles · ultra-rare exomes 192/1,460,752 · genomes 3/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0161%	6,210
Remaining individualsnot grpmax-eligible	0.00641%	15,605
South Asian	0.0011%	90,994

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.Pro358=
Coding: c.1074G>A
MANE Select: NM_003072
dbSNP: rs374167170
Type: single nucleotide variant
Location: chr19:10987880 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB

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.Pro358Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro358Ser 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
SMARCA4 c.3216-2A>G Likely pathogenic ★★ same condition
SMARCA4 c.3546+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-pro358 (accessed [today's date]).

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