Is CDH12 p.Pro283Ala (c.847C>G) pathogenic?

CDH12 p.Pro283Ala (c.847C>G) is classified Uncertain significance in CDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-04). AlphaMissense: likely benign (0.0555); Rare (popmax 0.109%, amr).

How common is CDH12 p.Pro283Ala (c.847C>G) in the general population?

CDH12 p.Pro283Ala (c.847C>G) is rare (popmax 0.109%, amr) (gnomAD).

What do computational predictors say about CDH12 p.Pro283Ala (c.847C>G)?

AlphaMissense predicts likely benign (score 0.0555) — an in-silico prediction, not a clinical call.

CDH12 p.Pro283Ala

c.847C>G · rs747709119 · VCV2389595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0555 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0555	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.38	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 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 223 kb · p 0.95 · regional, not allelic
Overall
CADD	19.81	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 0.109% Admixed American · 65/59,618 alleles

Filtering AF 0.0877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.08%

Overall 0.00602% 97/1,611,206 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.109%	917
Middle Eastern	0.0495%	2,022
Remaining individualsnot grpmax-eligible	0.0289%	3,464
South Asian	0.00221%	45,314
European (non-Finnish)	0.000763%	130,979

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: CDH12
Protein: p.Pro283Ala
Coding: c.847C>G
MANE Select: NM_004061
dbSNP: rs747709119
Type: single nucleotide variant
Location: chr5:21817100 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 283: 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-pro283ala (accessed [today's date]).

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