Is CADM3 p.Ala331Asp (c.992C>A) pathogenic?

CADM3 p.Ala331Asp (c.992C>A) is classified Uncertain significance in CADM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). AlphaMissense: likely pathogenic (0.9385); Very rare (popmax 8.47e-05%, nfe).

How common is CADM3 p.Ala331Asp (c.992C>A) in the general population?

CADM3 p.Ala331Asp (c.992C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CADM3 p.Ala331Asp (c.992C>A)?

AlphaMissense predicts likely pathogenic (score 0.9385) — an in-silico prediction, not a clinical call.

CADM3 p.Ala331Asp

c.992C>A · VCV4534424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9385 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9385	likely pathogenic
REVEL	0.503	indeterminate
SaProt	LLR -13.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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 0.76	unconstrained · MANE · 8,978 bp · p 2.3e-07 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,888 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: CADM3
Protein: p.Ala331Asp
Coding: c.992C>A
MANE Select: NM_001127173
Type: single nucleotide variant
Location: chr1:159199790 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.97 · 1 PDB

Full CADM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CADM3 p.Ala331Thr Uncertain significance ★ ⚠ same residue
CADM3 p.Tyr138Cys Likely pathogenic ★★ ⚠ same type
CADM3 c.89-2102C>T Uncertain significance ★★ same type
CADM3 p.Leu13Gln Uncertain significance ★★ ⚠ same type
CADM3 p.Tyr354Cys Uncertain significance ★★ ⚠ same type
CADM3 c.229+11A>G Uncertain significance ★ same type
CADM3 c.382+1G>A Uncertain significance ★ same type
CADM3 c.89-2118G>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/cadm3-p-ala331asp (accessed [today's date]).

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