Is CSMD2 p.Gln140Lys (c.418C>A) pathogenic?

CSMD2 p.Gln140Lys (c.418C>A) is classified Uncertain significance in CSMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.1855); Very rare (popmax 0.00223%, nfe).

How common is CSMD2 p.Gln140Lys (c.418C>A) in the general population?

CSMD2 p.Gln140Lys (c.418C>A) is very rare (popmax 0.00223%, nfe) (gnomAD).

What do computational predictors say about CSMD2 p.Gln140Lys (c.418C>A)?

AlphaMissense predicts likely benign (score 0.1855) — an in-silico prediction, not a clinical call.

CSMD2 p.Gln140Lys

c.418C>A · VCV4235015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1855	likely benign
REVEL	0.155	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 132 kb · p 0.023 · regional, not allelic
Overall
CADD	28.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q100K vs ClinVar Q140K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% European (non-Finnish) · 26/1,167,276 alleles

Filtering AF 0.00155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00132%

Overall 0.00176% 28/1,589,290 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00223%	44,895
Remaining individualsnot grpmax-eligible	0.00162%	61,584
African / African-American	0.00134%	74,672

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.Gln140Lys
Coding: c.418C>A
MANE Select: NM_001281956
Type: single nucleotide variant
Location: chr1:34032693 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Residue 140: the sushi 1 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-gln140lys (accessed [today's date]).

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