Is CLDN2 p.Phe158Tyr (c.473T>A) pathogenic?

CLDN2 p.Phe158Tyr (c.473T>A) is classified Likely benign in CLDN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-16). AlphaMissense: likely benign (0.0811); Rare (popmax 0.747%, afr).

How common is CLDN2 p.Phe158Tyr (c.473T>A) in the general population?

CLDN2 p.Phe158Tyr (c.473T>A) is rare (popmax 0.747%, afr) (gnomAD).

What do computational predictors say about CLDN2 p.Phe158Tyr (c.473T>A)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

CLDN2 p.Phe158Tyr

c.473T>A · rs150418351 · VCV777817

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.747%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -5.25	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 1.2	GERP -1.5, phastCons 0.98
Regional constraint	o/e 0.80	unconstrained · MANE · 404 bp · p 0.049 · regional, not allelic
Overall
CADD	9.551	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 0.747% African / African-American · 427/57,160 alleles

Filtering AF 0.688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.665%

Overall 0.0407% 492/1,209,703 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.747%	134
Admixed American	0.059%	1,695
Remaining individualsnot grpmax-eligible	0.0504%	1,984
South Asian	0.00176%	56,751
European (non-Finnish)	0.00145%	68,845

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: CLDN2
Protein: p.Phe158Tyr
Coding: c.473T>A
MANE Select: NM_020384
dbSNP: rs150418351
Type: single nucleotide variant
Location: chrX:106928701 (GRCh38)
Structure: AlphaFold pLDDT 78.99 · 1 PDB

Full CLDN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIPPLY1 p.Thr83= Benign ★★ same type
RIPPLY1 p.Tyr131= Benign ★★ same type
CLDN2 p.Ala89Thr Uncertain significance ★ ⚠ same type
CLDN2 p.Asp154Glu Uncertain significance ★ ⚠ same type
CLDN2 p.Gly10Ala Uncertain significance ★ ⚠ same type
CLDN2 p.Leu164Val Uncertain significance ★ ⚠ same type
CLDN2 p.Lys216Glu Uncertain significance ★ ⚠ same type
CLDN2 p.Pro209Thr 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/cldn2-p-phe158tyr (accessed [today's date]).

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