Is CSMD2 p.Ala227Thr (c.679G>A) pathogenic?

CSMD2 p.Ala227Thr (c.679G>A) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.2955); Rare (popmax 0.129%, eas).

How common is CSMD2 p.Ala227Thr (c.679G>A) in the general population?

CSMD2 p.Ala227Thr (c.679G>A) is rare (popmax 0.129%, eas) (gnomAD).

What do computational predictors say about CSMD2 p.Ala227Thr (c.679G>A)?

AlphaMissense predicts likely benign (score 0.2955) — an in-silico prediction, not a clinical call.

CSMD2 p.Ala227Thr

c.679G>A · rs184529652 · VCV2518770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2955 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.129%, eas)

Computational evidence

Protein change
AlphaMissense	0.2955	likely benign
REVEL	0.291	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 331 kb · p 5.5e-29 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A187T vs ClinVar A227T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.129% East Asian · 58/44,864 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0931%

Overall 0.00583% 94/1,612,330 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.129%	774
Remaining individualsnot grpmax-eligible	0.00801%	12,488
African / African-American	0.008%	12,502
European (non-Finnish)	0.00204%	49,128
South Asian	0.0011%	90,744

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: CSMD2
Protein: p.Ala227Thr
Coding: c.679G>A
MANE Select: NM_001281956
dbSNP: rs184529652
Type: single nucleotide variant
Location: chr1:33935793 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 227: the cub 2 domain; a disulfide bond

Full CSMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSMD2 p.Pro1506= Likely benign ★★ same type
CSMD2 p.Ser3015= Benign ★★ same type
CSMD2 c.404+2T>A Uncertain significance ★ same type
CSMD2 c.6344-398G>T Uncertain significance ★ same type
CSMD2 c.6344-422A>G Uncertain significance ★ same type
CSMD2 c.6344-423T>C Uncertain significance ★ same type
CSMD2 c.6344-429G>A Uncertain significance ★ same type
CSMD2 c.6344-435G>A Uncertain significance ★ 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/csmd2-p-ala227thr (accessed [today's date]).

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