Is CDH19 p.Val138Ala (c.413T>C) pathogenic?

CDH19 p.Val138Ala (c.413T>C) is classified Uncertain significance in CDH19 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.841); Ultra-rare (popmax 0.0655%, afr).

How common is CDH19 p.Val138Ala (c.413T>C) in the general population?

CDH19 p.Val138Ala (c.413T>C) is ultra-rare (popmax 0.0655%, afr) (gnomAD).

What do computational predictors say about CDH19 p.Val138Ala (c.413T>C)?

AlphaMissense predicts likely pathogenic (score 0.841) — an in-silico prediction, not a clinical call.

CDH19 p.Val138Ala

c.413T>C · rs371102409 · VCV3141180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0655%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.841	likely pathogenic · top 9% in CDH19
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 67 kb · p 0.00092 · regional, not allelic
Overall
CADD	27.1	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 0.0655% African / African-American · 49/74,862 alleles

Filtering AF 0.0508% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0456%

Overall 0.00316% 51/1,612,290 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0655%	1,528
Remaining individualsnot grpmax-eligible	0.0032%	31,203

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: CDH19
Protein: p.Val138Ala
Coding: c.413T>C
MANE Select: NM_021153
dbSNP: rs371102409
Type: single nucleotide variant
Location: chr18:66568493 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.14
Residue 138: the cadherin 1 domain

Full CDH19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH19 p.Pro558= Benign ★★ same type
CDH19 p.Thr89Ile Benign ★★ same type
CDH7 c.1612+22C>T Benign ★★ same type
CDH7 c.1612+24A>T Benign ★★ same type
CDH7 c.1612+81T>C Benign ★★ same type
CDH7 c.1864+225A>G Benign ★★ same type
CDH7 c.210+52G>A Benign ★★ same type
CDH7 c.210+56T>G 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/cdh19-p-val138ala (accessed [today's date]).

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