Is CDH19 p.Tyr196Cys (c.587A>G) pathogenic?

CDH19 p.Tyr196Cys (c.587A>G) is classified Uncertain significance in CDH19 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely benign (0.2673); Very rare (popmax 8.49e-05%, nfe).

How common is CDH19 p.Tyr196Cys (c.587A>G) in the general population?

CDH19 p.Tyr196Cys (c.587A>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CDH19 p.Tyr196Cys (c.587A>G)?

AlphaMissense predicts likely benign (score 0.2673) — an in-silico prediction, not a clinical call.

CDH19 p.Tyr196Cys

c.587A>G · rs2511859972 · VCV2271834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2673	likely benign
REVEL	0.66	pathogenic-leaning
SaProt	LLR -13.50	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 67 kb · p 0.00092 · regional, not allelic
Overall
CADD	28.2	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 8.49e-05% European (non-Finnish) · 1/1,178,508 alleles

Overall 6.85e-05% 1/1,459,676 alleles · very rare

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.Tyr196Cys
Coding: c.587A>G
MANE Select: NM_021153
dbSNP: rs2511859972
Type: single nucleotide variant
Location: chr18:66554428 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.14
Residue 196: the cadherin 2 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-tyr196cys (accessed [today's date]).

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