Is SMARCD2 p.Met375Val (c.1123A>G) pathogenic?

SMARCD2 p.Met375Val (c.1123A>G) is classified Uncertain significance in SMARCD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: likely benign (0.0707); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMARCD2 p.Met375Val (c.1123A>G)?

SMARCD2 p.Met375Val (c.1123A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SMARCD2 p.Met375Val (c.1123A>G) in the general population?

SMARCD2 p.Met375Val (c.1123A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about SMARCD2 p.Met375Val (c.1123A>G)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

SMARCD2 p.Met375Val

c.1123A>G · VCV3798990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.12, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 9,733 bp · p 8.5e-11 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,936 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000744% 12/1,613,862 alleles · very rare exomes 5/1,461,648 · genomes 7/152,214 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,489
European (non-Finnish)	0.000509%	196,643

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: SMARCD2
Protein: p.Met375Val
Coding: c.1123A>G
MANE Select: NM_001098426
Type: single nucleotide variant
Location: chr17:63833967 (GRCh38)
Gene constraint: LOEUF 0.762 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.38
Residue 375: the swib/mdm2 domain

Full SMARCD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMARCD2 p.Met375Leu Uncertain significance ★ ⚠ same residue
SMARCD2 p.Ala434Thr Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg118Cys Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg148Gln Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg175His Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg360Cys Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg473Leu Uncertain significance ★★ ⚠ same condition
SMARCD2 p.Arg476Cys Uncertain significance ★★ ⚠ 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/smarcd2-p-met375val (accessed [today's date]).

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