Is CLDN7 p.Pro28Leu (c.83C>T) pathogenic?

CLDN7 p.Pro28Leu (c.83C>T) is classified Uncertain significance in CLDN7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely pathogenic (0.9685); Very rare (popmax 0.00127%, nfe).

How common is CLDN7 p.Pro28Leu (c.83C>T) in the general population?

CLDN7 p.Pro28Leu (c.83C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about CLDN7 p.Pro28Leu (c.83C>T)?

AlphaMissense predicts likely pathogenic (score 0.9685) — an in-silico prediction, not a clinical call.

CLDN7 p.Pro28Leu

c.83C>T · rs763080763 · VCV2336570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9685	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -16.15	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 10	GERP 2.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 173 bp · p 0.00092 · regional, not allelic
Overall
CADD	31.0	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 0.00127% European (non-Finnish) · 15/1,180,024 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00109% 16/1,461,716 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.00127%	78,668

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLDN7
Protein: p.Pro28Leu
Coding: c.83C>T
MANE Select: NM_001307
dbSNP: rs763080763
Type: single nucleotide variant
Location: chr17:7261961 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.45

Full CLDN7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN7 p.Ala133Pro Uncertain significance ★ ⚠ same type
CLDN7 p.Ala170Thr Uncertain significance ★ ⚠ same type
CLDN7 p.Ala180Thr Uncertain significance ★ ⚠ same type
CLDN7 p.Ala79Asp Uncertain significance ★ ⚠ same type
CLDN7 p.Arg106Leu Uncertain significance ★ same type
CLDN7 p.Arg199Cys Uncertain significance ★ same type
CLDN7 p.Arg199Gly Uncertain significance ★ ⚠ same type
CLDN7 p.Asn39Ile 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/cldn7-p-pro28leu (accessed [today's date]).

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