Is CLDN25 p.Val55Ala (c.164T>C) pathogenic?

CLDN25 p.Val55Ala (c.164T>C) is classified Uncertain significance in CLDN25 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2428); Very rare (popmax 0.00333%, amr).

How common is CLDN25 p.Val55Ala (c.164T>C) in the general population?

CLDN25 p.Val55Ala (c.164T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CLDN25 p.Val55Ala (c.164T>C)?

AlphaMissense predicts likely benign (score 0.2428) — an in-silico prediction, not a clinical call.

CLDN25 p.Val55Ala

c.164T>C · VCV4229594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2428	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -10.07	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 3.1	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 686 bp · p 0.7 · regional, not allelic
Overall
CADD	21.4	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 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00131% 2/152,166 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: CLDN25
Protein: p.Val55Ala
Coding: c.164T>C
MANE Select: NM_001101389
Type: single nucleotide variant
Location: chr11:113779959 (GRCh38)
Gene constraint: LOEUF 1.892 · pLI 0.29 (gnomAD)
Structure: AlphaFold pLDDT 82.88

Full CLDN25 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN25 p.Ala143Ser Uncertain significance ★ ⚠ same type
CLDN25 p.Ala171Thr Uncertain significance ★ ⚠ same type
CLDN25 p.Ala61Asp Uncertain significance ★ ⚠ same type
CLDN25 p.Arg117Gln Uncertain significance ★ ⚠ same type
CLDN25 p.Arg117Trp Uncertain significance ★ ⚠ same type
CLDN25 p.Asn41Lys Uncertain significance ★ ⚠ same type
CLDN25 p.Asp147Asn Uncertain significance ★ ⚠ same type
CLDN25 p.Asp147His 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/cldn25-p-val55ala (accessed [today's date]).

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