Is CDH12 p.Ala548Val (c.1643C>T) pathogenic?

CDH12 p.Ala548Val (c.1643C>T) is classified Uncertain significance in CDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely pathogenic (0.6259); Very rare (popmax 0.00271%, nfe).

How common is CDH12 p.Ala548Val (c.1643C>T) in the general population?

CDH12 p.Ala548Val (c.1643C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about CDH12 p.Ala548Val (c.1643C>T)?

AlphaMissense predicts likely pathogenic (score 0.6259) — an in-silico prediction, not a clinical call.

CDH12 p.Ala548Val

c.1643C>T · VCV3265168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6259	likely pathogenic
REVEL	0.579	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 223 kb · p 0.95 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00271% European (non-Finnish) · 32/1,179,842 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00223% 36/1,613,752 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)grpmax	0.00271%	36,870
South Asian	0.0011%	91,082

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala548Val
Coding: c.1643C>T
MANE Select: NM_004061
Type: single nucleotide variant
Location: chr5:21755833 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 548: the cadherin 5 domain

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

Similar variants

CDH12 p.Ala548= Likely benign ★ same residue
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

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-ala548val (accessed [today's date]).

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