Is CADM4 p.Ala302Pro (c.904G>C) pathogenic?

CADM4 p.Ala302Pro (c.904G>C) is classified Uncertain significance in CADM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely pathogenic (0.9739); Very rare (popmax 0.000254%, nfe).

How common is CADM4 p.Ala302Pro (c.904G>C) in the general population?

CADM4 p.Ala302Pro (c.904G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CADM4 p.Ala302Pro (c.904G>C)?

AlphaMissense predicts likely pathogenic (score 0.9739) — an in-silico prediction, not a clinical call.

CADM4 p.Ala302Pro

c.904G>C · VCV4218163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9739	likely pathogenic · top 10% in CADM4
REVEL	0.269	benign-leaning
SaProt	LLR -14.91	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 16 kb · p 3.1e-06 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,452 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,676 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: CADM4
Protein: p.Ala302Pro
Coding: c.904G>C
MANE Select: NM_145296
Type: single nucleotide variant
Location: chr19:43625102 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 85.31
Residue 302: the ig-like c2-type 2 domain

Full CADM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CADM4 p.Ala201Thr Uncertain significance ★ ⚠ same type
CADM4 p.Ala324Pro Uncertain significance ★ ⚠ same type
CADM4 p.Ala324Thr Uncertain significance ★ ⚠ same type
CADM4 p.Ala4Thr Uncertain significance ★ ⚠ same type
CADM4 p.Ala60Asp Uncertain significance ★ ⚠ same type
CADM4 p.Arg190His Uncertain significance ★ ⚠ same type
CADM4 p.Arg257Gly Uncertain significance ★ ⚠ same type
CADM4 p.Arg45Gly 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/cadm4-p-ala302pro (accessed [today's date]).

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