Is CDH19 p.Pro130Leu (c.389C>T) pathogenic?

CDH19 p.Pro130Leu (c.389C>T) is classified Uncertain significance in CDH19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.1434); Ultra-rare (popmax 0.0461%, sas).

How common is CDH19 p.Pro130Leu (c.389C>T) in the general population?

CDH19 p.Pro130Leu (c.389C>T) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about CDH19 p.Pro130Leu (c.389C>T)?

AlphaMissense predicts likely benign (score 0.1434) — an in-silico prediction, not a clinical call.

CDH19 p.Pro130Leu

c.389C>T · VCV4223775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1434 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1434	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 67 kb · p 0.00092 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0461% South Asian · 42/91,044 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00292% 47/1,612,284 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.00641%	15,604
European (non-Finnish)	8.48e-05%	1,178,938

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.Pro130Leu
Coding: c.389C>T
MANE Select: NM_021153
Type: single nucleotide variant
Location: chr18:66568517 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.14
Residue 130: the cadherin 1 domain

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

Similar variants

CDH19 p.Pro130Thr Uncertain significance ★ ⚠ same residue
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

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-pro130leu (accessed [today's date]).

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