Is CLDN8 p.Ala94Val (c.281C>T) pathogenic?

CLDN8 p.Ala94Val (c.281C>T) is classified Benign in CLDN8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-03). AlphaMissense: likely pathogenic (0.6721); Low-frequency (popmax 4.78%, afr).

How common is CLDN8 p.Ala94Val (c.281C>T) in the general population?

CLDN8 p.Ala94Val (c.281C>T) is low-frequency (popmax 4.78%, afr) (gnomAD).

What do computational predictors say about CLDN8 p.Ala94Val (c.281C>T)?

AlphaMissense predicts likely pathogenic (score 0.6721) — an in-silico prediction, not a clinical call.

CLDN8 p.Ala94Val

c.281C>T · rs61743791 · VCV769122

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6721 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.78%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6721	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 674 bp · p 0.046 · regional, not allelic
Overall
CADD	24.9	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 4.78% African / African-American · 3,583/75,008 alleles

Filtering AF 4.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.59%

Overall 0.273% 4,412/1,614,046 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.78%	21
Middle Eastern	0.577%	173
Admixed American	0.438%	228
Remaining individualsnot grpmax-eligible	0.386%	259
European (non-Finnish)	0.0235%	4,260
South Asian	0.0121%	8,279
Finnishnot grpmax-eligible	0.00313%	31,997

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.Ala94Val
Coding: c.281C>T
MANE Select: NM_199328
dbSNP: rs61743791
Type: single nucleotide variant
Location: chr21:30215645 (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.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
CLDN8 p.Gly109Glu 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-ala94val (accessed [today's date]).

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