Is CLDN23 p.Arg237Ser (c.709C>A) pathogenic?

CLDN23 p.Arg237Ser (c.709C>A) is classified Uncertain significance in CLDN23 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). AlphaMissense: likely benign (0.1319); Very rare (popmax 0.000953%, nfe).

How common is CLDN23 p.Arg237Ser (c.709C>A) in the general population?

CLDN23 p.Arg237Ser (c.709C>A) is very rare (popmax 0.000953%, nfe) (gnomAD).

What do computational predictors say about CLDN23 p.Arg237Ser (c.709C>A)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

CLDN23 p.Arg237Ser

c.709C>A · rs935224815 · VCV2522189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000953%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.00	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 -3.3	GERP -3
Regional constraint	o/e 1.38	unconstrained · MANE · 875 bp · p 4.1e-15 · regional, not allelic
Overall
CADD	0.225	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

Grpmax group 0.000953% European (non-Finnish) · 11/1,154,396 alleles

Filtering AF 0.000511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000374%

Overall 0.000712% 11/1,545,180 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.Arg237Ser
Coding: c.709C>A
MANE Select: NM_194284
dbSNP: rs935224815
Type: single nucleotide variant
Location: chr8:8703107 (GRCh38)
Gene constraint: LOEUF 1.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.64
Residue 237: the 'disordered' region

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-arg237ser (accessed [today's date]).

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