Is CLDN34 p.Pro47Ala (c.139C>G) pathogenic?

CLDN34 p.Pro47Ala (c.139C>G) is classified Uncertain significance in CLDN34 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.0788); Ultra-rare (popmax 0.0144%, afr).

How common is CLDN34 p.Pro47Ala (c.139C>G) in the general population?

CLDN34 p.Pro47Ala (c.139C>G) is ultra-rare (popmax 0.0144%, afr) (gnomAD).

What do computational predictors say about CLDN34 p.Pro47Ala (c.139C>G)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

CLDN34 p.Pro47Ala

c.139C>G · VCV4003433

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -4.34	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 -13	GERP -2.2
Regional constraint	o/e 0.97	unconstrained · MANE · 641 bp · p 0.67 · regional, not allelic
Overall
CADD	0.012	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 0.0144% African / African-American · 8/55,470 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.000867% 10/1,153,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0144%	6,934
European (non-Finnish)	0.000229%	436,247

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: CLDN34
Protein: p.Pro47Ala
Coding: c.139C>G
MANE Select: NM_001195081
Type: single nucleotide variant
Location: chrX:9967496 (GRCh38)
Structure: AlphaFold pLDDT 86.14

Full CLDN34 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN34 p.Pro47Thr Uncertain significance ★ ⚠ same residue
CLDN34 p.Ala105Gly Uncertain significance ★ ⚠ same type
CLDN34 p.Ala137Val Uncertain significance ★ ⚠ same type
CLDN34 p.Ala50Thr Uncertain significance ★ ⚠ same type
CLDN34 p.Arg63Cys Uncertain significance ★ ⚠ same type
CLDN34 p.Arg63Gly Uncertain significance ★ ⚠ same type
CLDN34 p.Arg63Leu Uncertain significance ★ ⚠ same type
CLDN34 p.Arg74Gln 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/cldn34-p-pro47ala (accessed [today's date]).

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