Is CLDN5 p.Cys104Ser (c.311G>C) pathogenic?

CLDN5 p.Cys104Ser (c.311G>C) is classified Uncertain significance in CLDN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.8449); Absent from gnomAD v4.1.

How common is CLDN5 p.Cys104Ser (c.311G>C) in the general population?

CLDN5 p.Cys104Ser (c.311G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLDN5 p.Cys104Ser (c.311G>C)?

AlphaMissense predicts likely pathogenic (score 0.8449) — an in-silico prediction, not a clinical call.

CLDN5 p.Cys104Ser

c.311G>C · VCV4088088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8449 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8449	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -11.48	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 441 bp · p 0.0013 · regional, not allelic
Overall
CADD	29.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLDN5
Protein: p.Cys104Ser
Coding: c.311G>C
MANE Select: NM_001363066
Type: single nucleotide variant
Location: chr22:19523945 (GRCh38)
Gene constraint: LOEUF 1.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42

Full CLDN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN5 p.Gly60Arg Pathogenic ★★ same type
CLDN5 p.Val41Met Pathogenic ★★ same type
CLDN5 c.*67G>T Benign ★★ same type
CLDN5 p.Gly101= Benign ★★ same type
CLDN5 p.Ser58Arg Likely pathogenic ★ same type
CLDN5 p.Thr59Ile Pathogenic ★ same type
CLDN5 c.-104G>T Uncertain significance ★ same type
CLDN5 c.-131C>A 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/cldn5-p-cys104ser (accessed [today's date]).

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