Is SMARCA4 p.Pro49= (c.147G>A) pathogenic?

SMARCA4 p.Pro49= (c.147G>A) is classified Benign/Likely benign in SMARCA4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-09). Very rare (popmax 0.00444%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCA4 p.Pro49= (c.147G>A)?

SMARCA4 p.Pro49= (c.147G>A) is associated with hereditary neoplastic syndrome, rhabdoid tumor predisposition syndrome 2, intellectual disability, autosomal dominant 16 (ClinVar).

How common is SMARCA4 p.Pro49= (c.147G>A) in the general population?

SMARCA4 p.Pro49= (c.147G>A) is very rare (popmax 0.00444%, sas) (gnomAD).

SMARCA4 p.Pro49=

c.147G>A · rs758438795 · VCV328018

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00444%, sas)

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 -0.59	GERP -4.3, phastCons 0.037
Overall
CADD	3.081	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00444% South Asian · 4/90,056 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00218% 35/1,607,230 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00444%	22,514
European (non-Finnish)	0.00246%	40,599
East Asian	0.00224%	44,642
African / African-American	0.00134%	74,818

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.Pro49=
Coding: c.147G>A
MANE Select: NM_003072
dbSNP: rs758438795
Type: single nucleotide variant
Location: chr19:10984298 (GRCh38)
Gene constraint: LOEUF 0.226 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 31 PDB
Residue 49: 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 intellectual disability, autosomal dominant 16 Coffin-Siris syndrome

Similar variants

SMARCA4 p.Pro49Leu Uncertain significance ★★ ⚠ same residue
SMARCA4 p.Pro49Arg Uncertain significance ★ ⚠ same residue
SMARCA4 p.Pro49Ser 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-pro49 (accessed [today's date]).

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