Is CLDN23 p.Pro4Ser (c.10C>T) pathogenic?

CLDN23 p.Pro4Ser (c.10C>T) is classified Uncertain significance in CLDN23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: ambiguous (0.4301); Very rare (popmax 0.000177%, nfe).

How common is CLDN23 p.Pro4Ser (c.10C>T) in the general population?

CLDN23 p.Pro4Ser (c.10C>T) is very rare (popmax 0.000177%, nfe) (gnomAD).

What do computational predictors say about CLDN23 p.Pro4Ser (c.10C>T)?

AlphaMissense predicts ambiguous (score 0.4301) — an in-silico prediction, not a clinical call.

CLDN23 p.Pro4Ser

c.10C>T · VCV4003417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000177%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4301	ambiguous
REVEL	0.361	indeterminate
SaProt	LLR -6.27	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 875 bp · p 4.1e-15 · regional, not allelic
Overall
CADD	26.6	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 0.000177% European (non-Finnish) · 2/1,126,868 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000148% 2/1,347,080 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: CLDN23
Protein: p.Pro4Ser
Coding: c.10C>T
MANE Select: NM_194284
Type: single nucleotide variant
Location: chr8:8702408 (GRCh38)
Gene constraint: LOEUF 1.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.64

Full CLDN23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN23 p.Ala149Pro Uncertain significance ★ ⚠ same type
CLDN23 p.Ala14Val Uncertain significance ★ ⚠ same type
CLDN23 p.Ala198Thr Uncertain significance ★ ⚠ same type
CLDN23 p.Ala27Gly Uncertain significance ★ ⚠ same type
CLDN23 p.Ala74Asp Uncertain significance ★ ⚠ same type
CLDN23 p.Ala82Thr Uncertain significance ★ ⚠ same type
CLDN23 p.Arg188Cys Uncertain significance ★ ⚠ same type
CLDN23 p.Arg193Cys 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/cldn23-p-pro4ser (accessed [today's date]).

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