Is CADM4 p.Ala324Pro (c.970G>C) pathogenic?

CADM4 p.Ala324Pro (c.970G>C) is classified Uncertain significance in CADM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.7853); Ultra-rare (popmax 0.012%, afr).

How common is CADM4 p.Ala324Pro (c.970G>C) in the general population?

CADM4 p.Ala324Pro (c.970G>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CADM4 p.Ala324Pro (c.970G>C)?

AlphaMissense predicts likely pathogenic (score 0.7853) — an in-silico prediction, not a clinical call.

CADM4 p.Ala324Pro

c.970G>C · VCV4218162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7853	likely pathogenic
REVEL	0.389	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 16 kb · p 3.1e-06 · regional, not allelic
Overall
CADD	27.8	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 0.012% African / African-American · 9/75,066 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000681% 11/1,614,222 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,341
Admixed American	0.00167%	60,020
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ala324Pro
Coding: c.970G>C
MANE Select: NM_145296
Type: single nucleotide variant
Location: chr19:43624201 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 85.31

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

Similar variants

CADM4 p.Ala324Thr Uncertain significance ★ ⚠ same residue
CADM4 p.Ala201Thr Uncertain significance ★ ⚠ same type
CADM4 p.Ala302Pro 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-ala324pro (accessed [today's date]).

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