Is CLDN12 p.Phe25Val (c.73T>G) pathogenic?

CLDN12 p.Phe25Val (c.73T>G) is classified Uncertain significance in CLDN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.1647); Very rare (popmax 8.47e-05%, nfe).

How common is CLDN12 p.Phe25Val (c.73T>G) in the general population?

CLDN12 p.Phe25Val (c.73T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLDN12 p.Phe25Val (c.73T>G)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

CLDN12 p.Phe25Val

c.73T>G · VCV4003387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 3.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 731 bp · p 0.00019 · regional, not allelic
Overall
CADD	19.55	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,888 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: CLDN12
Protein: p.Phe25Val
Coding: c.73T>G
MANE Select: NM_001185072
Type: single nucleotide variant
Location: chr7:90412749 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.85

Full CLDN12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN12 p.Ala8Thr Uncertain significance ★ ⚠ same type
CLDN12 p.Arg37Gln Uncertain significance ★ ⚠ same type
CLDN12 p.Arg4Trp Uncertain significance ★ ⚠ same type
CLDN12 p.Gly17Arg Uncertain significance ★ ⚠ same type
CLDN12 p.Gly63Arg Uncertain significance ★ ⚠ same type
CLDN12 p.Ile179Val Uncertain significance ★ ⚠ same type
CLDN12 p.Ile96Met Uncertain significance ★ ⚠ same type
CLDN12 p.Leu122Gln 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/cldn12-p-phe25val (accessed [today's date]).

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