Is CADM2 p.Ala69Ser (c.205G>T) pathogenic?

CADM2 p.Ala69Ser (c.205G>T) is classified Uncertain significance in CADM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: likely benign (0.1098); Ultra-rare (popmax 0.0217%, amr).

How common is CADM2 p.Ala69Ser (c.205G>T) in the general population?

CADM2 p.Ala69Ser (c.205G>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CADM2 p.Ala69Ser (c.205G>T)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

CADM2 p.Ala69Ser

c.205G>T · VCV3826824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -6.95	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 1,107 kb · p 2.6e-07 · regional, not allelic
Overall
CADD	32.0	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 A60S vs ClinVar A69S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,854 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000806% 13/1,612,624 alleles · ultra-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: CADM2
Protein: p.Ala69Ser
Coding: c.205G>T
MANE Select: NM_001167675
Type: single nucleotide variant
Location: chr3:85802163 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 82.53
Residue 69: a disulfide bond; the ig-like v-type domain

Full CADM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CADM2 c.970+17639A>G Benign ★★ same type
CADM2 p.Cys155= Benign ★★ same type
CADM2 c.970+17528A>T Uncertain significance ★ ⚠ same type
CADM2 c.970+17565C>A Uncertain significance ★ ⚠ same type
CADM2 c.970+17579A>G Uncertain significance ★ ⚠ same type
CADM2 c.970+17585G>A Uncertain significance ★ ⚠ same type
CADM2 p.Ala221Val Uncertain significance ★ ⚠ same type
CADM2 p.Ala316Val 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/cadm2-p-ala69ser (accessed [today's date]).

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