Is CLDN8 p.Ser208Arg (c.624T>G) pathogenic?

CLDN8 p.Ser208Arg (c.624T>G) is classified Likely benign in CLDN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely benign (0.2416); Rare (popmax 0.29%, nfe).

How common is CLDN8 p.Ser208Arg (c.624T>G) in the general population?

CLDN8 p.Ser208Arg (c.624T>G) is rare (popmax 0.29%, nfe) (gnomAD).

What do computational predictors say about CLDN8 p.Ser208Arg (c.624T>G)?

AlphaMissense predicts likely benign (score 0.2416) — an in-silico prediction, not a clinical call.

CLDN8 p.Ser208Arg

c.624T>G · VCV3390330

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2416 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.29%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2416	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.6, phastCons 0.84
Regional constraint	o/e 1.12	unconstrained · MANE · 674 bp · p 0.046 · regional, not allelic
Overall
CADD	14.91	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 0.29% European (non-Finnish) · 3,418/1,180,008 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.278%

Overall 0.234% 3,772/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.29%	345
Finnishnot grpmax-eligible	0.264%	379
Remaining individualsnot grpmax-eligible	0.162%	619
African / African-American	0.0626%	1,597
Admixed American	0.0566%	1,765
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803

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.Ser208Arg
Coding: c.624T>G
MANE Select: NM_199328
Type: single nucleotide variant
Location: chr21:30215302 (GRCh38)
Gene constraint: LOEUF 1.865 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 79.71
Residue 208: the 'disordered' region

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

Similar variants

CLDN8 p.Ser208Ile Uncertain significance ★ ⚠ same residue
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

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-ser208arg (accessed [today's date]).

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