Is SMARCB1 p.Ile245Met (c.735C>G) pathogenic?

SMARCB1 p.Ile245Met (c.735C>G) is classified Uncertain significance in SMARCB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1182); Very rare (popmax 0.00329%, sas).

How common is SMARCB1 p.Ile245Met (c.735C>G) in the general population?

SMARCB1 p.Ile245Met (c.735C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SMARCB1 p.Ile245Met (c.735C>G)?

AlphaMissense predicts likely benign (score 0.1182) — an in-silico prediction, not a clinical call.

SMARCB1 p.Ile245Met

c.735C>G · VCV4805976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1182	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -10.01	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -3.5
Overall
CADD	15.35	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,708 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.Ile245Met
Coding: c.735C>G
MANE Select: NM_003073
Type: single nucleotide variant
Location: chr22:23816876 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.77 · 17 PDB
Residue 245: an α-helix; the '2 x approximate tandem repeats' region; the 'myc-binding' region

Full SMARCB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMARCB1 p.Ile245= Likely benign ★★ same residue
SMARCB1 p.Ile245Thr Uncertain significance ★ ⚠ same residue
SMARCB1 p.Ile245Val Uncertain significance ★ ⚠ same residue
SMARCB1 c.795+1G>A Likely pathogenic ★★ same type
SMARCB1 c.93+1G>A Likely pathogenic ★★ same type
SMARCB1 c.986+1G>A Likely pathogenic ★★ same type
SMARCB1 c.986+2T>C Likely pathogenic ★★ same type
SMARCB1 c.*82C>T Pathogenic/Likely pathogenic ★★ same type

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-ile245met (accessed [today's date]).

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