Is CLDN4 p.Cys64Arg (c.190T>C) pathogenic?

CLDN4 p.Cys64Arg (c.190T>C) is classified Uncertain significance in CLDN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-14). AlphaMissense: likely pathogenic (0.9944); Very rare (popmax 0.00364%, nfe).

How common is CLDN4 p.Cys64Arg (c.190T>C) in the general population?

CLDN4 p.Cys64Arg (c.190T>C) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about CLDN4 p.Cys64Arg (c.190T>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

CLDN4 p.Cys64Arg

c.190T>C · rs781886975 · VCV2298547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 1% in CLDN4
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -13.61	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 6.2	GERP 4.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 626 bp · p 0.0085 · regional, not allelic
Overall
CADD	32.0	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 0.00364% European (non-Finnish) · 43/1,180,002 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00273% 44/1,613,986 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,442
African / African-American	0.00133%	74,946

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: CLDN4
Protein: p.Cys64Arg
Coding: c.190T>C
MANE Select: NM_001305
dbSNP: rs781886975
Type: single nucleotide variant
Location: chr7:73831391 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 8 PDB
Residue 64: the 'interaction with epha2' region; a disulfide bond; a β-strand

Full CLDN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN4 p.Ala113Thr Uncertain significance ★ ⚠ same type
CLDN4 p.Ala121Gly Uncertain significance ★ ⚠ same type
CLDN4 p.Ala12Pro Uncertain significance ★ ⚠ same type
CLDN4 p.Ala82Thr Uncertain significance ★ ⚠ same type
CLDN4 p.Arg81His Uncertain significance ★ ⚠ same type
CLDN4 p.Asp190Asn Uncertain significance ★ ⚠ same type
CLDN4 p.Asp76Glu Uncertain significance ★ ⚠ same type
CLDN4 p.Cys107Gly Uncertain significance ★ ⚠ 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/cldn4-p-cys64arg (accessed [today's date]).

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