Is CLDN15 p.Pro191Thr (c.571C>A) pathogenic?

CLDN15 p.Pro191Thr (c.571C>A) is classified Uncertain significance in CLDN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0582); Very rare (popmax 0.00721%, amr).

How common is CLDN15 p.Pro191Thr (c.571C>A) in the general population?

CLDN15 p.Pro191Thr (c.571C>A) is very rare (popmax 0.00721%, amr) (gnomAD).

What do computational predictors say about CLDN15 p.Pro191Thr (c.571C>A)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

CLDN15 p.Pro191Thr

c.571C>A · VCV4654128

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.57	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 1.3	GERP 1.9, phastCons 0.003
Regional constraint	o/e 0.81	unconstrained · MANE · 5,168 bp · p 0.00093 · regional, not allelic
Overall
CADD	10.39	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 0.00721% Admixed American · 4/55,494 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00188% 30/1,591,624 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00721%	13,873
Remaining individualsnot grpmax-eligible	0.00325%	30,771
European (non-Finnish)	0.00205%	48,726

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: CLDN15
Protein: p.Pro191Thr
Coding: c.571C>A
MANE Select: NM_014343
Type: single nucleotide variant
Location: chr7:101232614 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI 0.31 (gnomAD)
Structure: AlphaFold pLDDT 82.18

Full CLDN15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN15 p.Ala120Ser Uncertain significance ★ ⚠ same type
CLDN15 p.Ala134Thr Uncertain significance ★ ⚠ same type
CLDN15 p.Ala209Thr Uncertain significance ★ ⚠ same type
CLDN15 p.Ala85Thr Uncertain significance ★ ⚠ same type
CLDN15 p.Asp190Asn Uncertain significance ★ ⚠ same type
CLDN15 p.Gln213Glu Uncertain significance ★ ⚠ same type
CLDN15 p.Glu189Lys Uncertain significance ★ ⚠ same type
CLDN15 p.Glu214Gly 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/cldn15-p-pro191thr (accessed [today's date]).

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