Is SMARCA4 p.Ala503= (c.1509A>G) pathogenic?

SMARCA4 p.Ala503= (c.1509A>G) is classified Benign/Likely benign in SMARCA4 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Low-frequency (popmax 4.4%, nfe); Associated with otosclerosis 12.

What condition is associated with SMARCA4 p.Ala503= (c.1509A>G)?

SMARCA4 p.Ala503= (c.1509A>G) is associated with otosclerosis 12, rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16 (ClinVar).

How common is SMARCA4 p.Ala503= (c.1509A>G) in the general population?

SMARCA4 p.Ala503= (c.1509A>G) is low-frequency (popmax 4.4%, nfe) (gnomAD).

SMARCA4 p.Ala503=

c.1509A>G · rs17001075 · VCV126358

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.4%, nfe)

Conditions

otosclerosis 12

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 -8.8	GERP -4.4
Overall
CADD	0.341	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.4% European (non-Finnish) · 51,929/1,179,900 alleles

Filtering AF 4.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.36%

Overall 3.67% 59,197/1,614,068 alleles · low-frequency exomes 54,775/1,461,738 · genomes 4,422/152,330 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	4.4%	23
Remaining individualsnot grpmax-eligible	3.56%	28
African / African-American	2.15%	46
Middle Eastern	2.11%	47
Amishnot grpmax-eligible	1.97%	51
Ashkenazi Jewishnot grpmax-eligible	1.95%	51
Admixed American	1.94%	52
Finnishnot grpmax-eligible	1.76%	57
South Asian	0.446%	224
East Asian	0.00891%	11,221

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.Ala503=
Coding: c.1509A>G
MANE Select: NM_003072
dbSNP: rs17001075
Type: single nucleotide variant
Location: chr19:10994917 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 503: the hsa domain; the 'rna-binding region which is sufficient for binding to lncrna evf2' region

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

Disease context

otosclerosis 12 — 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 Coffin-Siris syndrome

Similar variants

SMARCA4 p.Ala503Thr 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
SMARCA4 c.3774+2T>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-ala503 (accessed [today's date]).

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