Is SMARCA4 p.His40= (c.120C>T) pathogenic?

SMARCA4 p.His40= (c.120C>T) is classified Benign/Likely benign in SMARCA4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.1%, sas); Associated with otosclerosis 12.

What condition is associated with SMARCA4 p.His40= (c.120C>T)?

SMARCA4 p.His40= (c.120C>T) is associated with otosclerosis 12, rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16 (ClinVar).

How common is SMARCA4 p.His40= (c.120C>T) in the general population?

SMARCA4 p.His40= (c.120C>T) is low-frequency (popmax 1.1%, sas) (gnomAD).

SMARCA4 p.His40=

c.120C>T · rs375884151 · VCV212233

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.1%, sas)

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 0.82	GERP 0.2, phastCons 1
Overall
CADD	7.945	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.1% South Asian · 997/90,722 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.02%

Overall 0.0675% 1,087/1,611,290 alleles · low-frequency exomes 1,035/1,458,956 · genomes 52/152,334 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.1%	91
Remaining individualsnot grpmax-eligible	0.111%	903
Middle Eastern	0.0335%	2,984
African / African-American	0.0107%	9,380
Admixed American	0.00335%	29,886
East Asian	0.00223%	44,836
European (non-Finnish)	0.000678%	147,397

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.His40=
Coding: c.120C>T
MANE Select: NM_003072
dbSNP: rs375884151
Type: single nucleotide variant
Location: chr19:10984271 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 40: 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

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.His40Arg Uncertain significance ★★ ⚠ same residue
SMARCA4 p.His40Gln Uncertain significance ★★ same residue
SMARCA4 p.His40Tyr 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

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-his40 (accessed [today's date]).

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