Is CLDN9 p.Ser53Phe (c.158C>T) pathogenic?

CLDN9 p.Ser53Phe (c.158C>T) is classified Uncertain significance in CLDN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.7794); Very rare (popmax 0.00161%, nfe).

How common is CLDN9 p.Ser53Phe (c.158C>T) in the general population?

CLDN9 p.Ser53Phe (c.158C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CLDN9 p.Ser53Phe (c.158C>T)?

AlphaMissense predicts likely pathogenic (score 0.7794) — an in-silico prediction, not a clinical call.

CLDN9 p.Ser53Phe

c.158C>T · VCV4229624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7794	likely pathogenic
REVEL	0.675	pathogenic-leaning
SaProt	LLR -12.69	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 4.1	GERP 0.6, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 650 bp · p 0.03 · regional, not allelic
Overall
CADD	26.2	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

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,012 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,870 alleles · very rare

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: CLDN9
Protein: p.Ser53Phe
Coding: c.158C>T
MANE Select: NM_020982
Type: single nucleotide variant
Location: chr16:3013520 (GRCh38)
Gene constraint: LOEUF 1.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.95 · 2 PDB
Residue 53: a β-strand

Full CLDN9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN9 p.Ser53Tyr Likely benign same residue
CLDN9 p.Arg205His Uncertain significance ★★ ⚠ same type
CLDN9 p.Ala170= Benign/Likely benign ★★ same type
CLDN9 p.Thr184= Likely benign ★★ same type
CLDN9 p.Arg116Cys Likely pathogenic ★ ⚠ same type
CLDN9 p.Ala115Thr Uncertain significance ★ ⚠ same type
CLDN9 p.Ala121Val Uncertain significance ★ ⚠ same type
CLDN9 p.Ala128Gly 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/cldn9-p-ser53phe (accessed [today's date]).

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