Is CLDN8 p.Pro28Ser (c.82C>T) pathogenic?

CLDN8 p.Pro28Ser (c.82C>T) is classified Uncertain significance in CLDN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely pathogenic (0.8606); Very rare (popmax 0.00891%, eas).

How common is CLDN8 p.Pro28Ser (c.82C>T) in the general population?

CLDN8 p.Pro28Ser (c.82C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CLDN8 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely pathogenic (score 0.8606) — an in-silico prediction, not a clinical call.

CLDN8 p.Pro28Ser

c.82C>T · rs753772677 · VCV2245782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8606	likely pathogenic
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -13.02	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 12	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 674 bp · p 0.046 · regional, not allelic
Overall
CADD	27.1	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 0.00891% East Asian · 4/44,876 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000496% 8/1,613,760 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,219
European (non-Finnish)	0.000339%	294,977

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: CLDN8
Protein: p.Pro28Ser
Coding: c.82C>T
MANE Select: NM_199328
dbSNP: rs753772677
Type: single nucleotide variant
Location: chr21:30215844 (GRCh38)
Gene constraint: LOEUF 1.865 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 79.71

Full CLDN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN8 p.Ala94Val Benign ★★ same type
CLDN8 p.Met97Thr Benign ★★ same type
CLDN8 p.Ala180Val Uncertain significance ★ ⚠ same type
CLDN8 p.Ala86Thr Uncertain significance ★ ⚠ same type
CLDN8 p.Asp110Asn Uncertain significance ★ ⚠ same type
CLDN8 p.Glu112Lys Uncertain significance ★ ⚠ same type
CLDN8 p.Glu190Gly Uncertain significance ★ ⚠ same type
CLDN8 p.Gly101Ser 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/cldn8-p-pro28ser (accessed [today's date]).

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