Is CDH12 p.Val309Ala (c.926T>C) pathogenic?

CDH12 p.Val309Ala (c.926T>C) is classified Uncertain significance in CDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.334); Absent from gnomAD v4.1.

How common is CDH12 p.Val309Ala (c.926T>C) in the general population?

CDH12 p.Val309Ala (c.926T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH12 p.Val309Ala (c.926T>C)?

AlphaMissense predicts likely benign (score 0.334) — an in-silico prediction, not a clinical call.

CDH12 p.Val309Ala

c.926T>C · VCV4223655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.334 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.334	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -8.04	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 6	GERP 0.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 223 kb · p 0.95 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH12
Protein: p.Val309Ala
Coding: c.926T>C
MANE Select: NM_004061
Type: single nucleotide variant
Location: chr5:21817021 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 309: the cadherin 3 domain

Full CDH12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH12 c.1003-3C>T Benign ★★ same type
CDH12 p.Asp780= Likely benign ★★ same type
CDH12 p.Gln60= Benign ★★ same type
CDH12 p.Glu349Asp Benign ★★ ⚠ same type
CDH12 p.Glu34Gln Benign ★★ same type
CDH12 p.Ile475Thr Benign ★★ ⚠ same type
CDH12 p.Ile598= Likely benign ★★ same type
CDH12 p.Pro213= Benign ★★ 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/cdh12-p-val309ala (accessed [today's date]).

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