Is CDH8 p.Ala332Thr (c.994G>A) pathogenic?

CDH8 p.Ala332Thr (c.994G>A) is classified Uncertain significance in CDH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0582); Very rare (popmax 0.00133%, afr).

How common is CDH8 p.Ala332Thr (c.994G>A) in the general population?

CDH8 p.Ala332Thr (c.994G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CDH8 p.Ala332Thr (c.994G>A)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

CDH8 p.Ala332Thr

c.994G>A · VCV4224003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -4.17	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 4.1	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 232 kb · p 1e-16 · regional, not allelic
Overall
CADD	17.85	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,936 alleles

Overall 0.000657% 1/152,110 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: CDH8
Protein: p.Ala332Thr
Coding: c.994G>A
MANE Select: NM_001796
Type: single nucleotide variant
Location: chr16:61820955 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.26
Residue 332: the cadherin 3 domain

Full CDH8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH8 p.Arg666Cys Likely benign ★★ same type
CDH8 p.Ile429= Benign ★★ same type
CDH8 p.Tyr667= Benign/Likely benign ★★ same type
CDH8 p.Ala30Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala443Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala502Gly Uncertain significance ★ ⚠ same type
CDH8 p.Ala629Val Uncertain significance ★ ⚠ same type
CDH8 p.Arg123Lys 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/cdh8-p-ala332thr (accessed [today's date]).

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