Is SMARCA4 p.Pro139= (c.417G>A) pathogenic?

SMARCA4 p.Pro139= (c.417G>A) is classified Likely benign in SMARCA4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-04). Ultra-rare (popmax 0.0493%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Pro139= (c.417G>A)?

SMARCA4 p.Pro139= (c.417G>A) is associated with hereditary neoplastic syndrome, rhabdoid tumor predisposition syndrome 2 (ClinVar).

How common is SMARCA4 p.Pro139= (c.417G>A) in the general population?

SMARCA4 p.Pro139= (c.417G>A) is ultra-rare (popmax 0.0493%, afr) (gnomAD).

SMARCA4 p.Pro139=

c.417G>A · rs142092395 · VCV415068

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, afr)

Conditions

hereditary neoplastic 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 -4.1
Overall
CADD	0.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% African / African-American · 37/75,058 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.00558% 90/1,613,924 alleles · ultra-rare exomes 62/1,461,626 · genomes 28/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0493%	2,029
Middle Eastern	0.033%	3,031
South Asian	0.0198%	5,061
Remaining individualsnot grpmax-eligible	0.0096%	10,417
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00178%	56,190

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.Pro139=
Coding: c.417G>A
MANE Select: NM_003072
dbSNP: rs142092395
Type: single nucleotide variant
Location: chr19:10986250 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 139: 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

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.Pro139Gln Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro139Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SMARCA4 p.Pro139Ser 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-pro139 (accessed [today's date]).

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