Is CLDN5 p.Phe196Val (c.586T>G) pathogenic?

CLDN5 p.Phe196Val (c.586T>G) is classified Uncertain significance in CLDN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.3267); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CLDN5 p.Phe196Val (c.586T>G)?

CLDN5 p.Phe196Val (c.586T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLDN5 p.Phe196Val (c.586T>G) in the general population?

CLDN5 p.Phe196Val (c.586T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLDN5 p.Phe196Val (c.586T>G)?

AlphaMissense predicts likely benign (score 0.3267) — an in-silico prediction, not a clinical call.

CLDN5 p.Phe196Val

c.586T>G · VCV4229607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3267 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3267	likely benign
REVEL	0.524	indeterminate
SaProt	LLR -4.09	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 9.1	GERP -1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 441 bp · p 0.0013 · regional, not allelic
Overall
CADD	23.2	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

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.Phe196Val
Coding: c.586T>G
MANE Select: NM_001363066
Type: single nucleotide variant
Location: chr22:19523670 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLDN5 p.Gly60Arg Pathogenic ★★ same condition
CLDN5 c.-104G>T Uncertain significance ★ same condition
CLDN5 c.-131C>A Uncertain significance ★ same condition
CLDN5 c.-29G>A Uncertain significance ★ same condition
CLDN5 c.-48G>A Uncertain significance ★ same condition
CLDN5 c.-6C>G Uncertain significance ★ same condition
CLDN5 c.-93G>C Uncertain significance ★ same condition
CLDN5 p.Ala4Thr Uncertain significance ★ ⚠ same condition

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-phe196val (accessed [today's date]).

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