Is CLDN8 p.Ile40Val (c.118A>G) pathogenic?

CLDN8 p.Ile40Val (c.118A>G) is classified Uncertain significance in CLDN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely benign (0.2762); Very rare (popmax 0.00167%, amr).

How common is CLDN8 p.Ile40Val (c.118A>G) in the general population?

CLDN8 p.Ile40Val (c.118A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLDN8 p.Ile40Val (c.118A>G)?

AlphaMissense predicts likely benign (score 0.2762) — an in-silico prediction, not a clinical call.

CLDN8 p.Ile40Val

c.118A>G · VCV4654190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2762	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 674 bp · p 0.046 · regional, not allelic
Overall
CADD	23.4	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 0.00167% Admixed American · 1/59,988 alleles

Overall 0.000124% 2/1,613,770 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Ile40Val
Coding: c.118A>G
MANE Select: NM_199328
Type: single nucleotide variant
Location: chr21:30215808 (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-ile40val (accessed [today's date]).

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