Is CLDN12 p.Trp207Cys (c.621G>T) pathogenic?

CLDN12 p.Trp207Cys (c.621G>T) is classified Uncertain significance in CLDN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely pathogenic (0.9864); Absent from gnomAD v4.1.

How common is CLDN12 p.Trp207Cys (c.621G>T) in the general population?

CLDN12 p.Trp207Cys (c.621G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLDN12 p.Trp207Cys (c.621G>T)?

AlphaMissense predicts likely pathogenic (score 0.9864) — an in-silico prediction, not a clinical call.

CLDN12 p.Trp207Cys

c.621G>T · VCV3833811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9864 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9864	likely pathogenic · top 8% in CLDN12
REVEL	0.635	indeterminate
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 731 bp · p 0.00019 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLDN12
Protein: p.Trp207Cys
Coding: c.621G>T
MANE Select: NM_001185072
Type: single nucleotide variant
Location: chr7:90413297 (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-trp207cys (accessed [today's date]).

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