Is SMARCB1 p.Pro249= (c.747C>T) pathogenic?

SMARCB1 p.Pro249= (c.747C>T) is classified Likely benign in SMARCB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-14). Very rare (popmax 0.000763%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with SMARCB1 p.Pro249= (c.747C>T)?

SMARCB1 p.Pro249= (c.747C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is SMARCB1 p.Pro249= (c.747C>T) in the general population?

SMARCB1 p.Pro249= (c.747C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

SMARCB1 p.Pro249=

c.747C>T · rs1555879356 · VCV486499

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

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 -1.7	GERP -3.5
Overall
CADD	8.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,980 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,784 alleles · very rare

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: SMARCB1
Protein: p.Pro249=
Coding: c.747C>T
MANE Select: NM_003073
dbSNP: rs1555879356
Type: single nucleotide variant
Location: chr22:23816888 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.77 · 17 PDB
Residue 249: an α-helix; the '2 x approximate tandem repeats' region

Full SMARCB1 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

Similar variants

SMARCB1 p.Pro249Thr Uncertain significance ★ ⚠ same residue
SMARCB1 p.Pro249Ser Uncertain significance ★ ⚠ same residue
SMARCB1 c.795+1G>A Likely pathogenic ★★ same condition
SMARCB1 c.93+1G>A Likely pathogenic ★★ same condition
SMARCB1 c.986+1G>A Likely pathogenic ★★ same condition
SMARCB1 c.*82C>T Pathogenic/Likely pathogenic ★★ same condition
SMARCB1 p.Arg158Ter Pathogenic ★★ same condition
SMARCB1 p.Arg201Ter 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/smarcb1-p-pro249 (accessed [today's date]).

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