Is CLDN15 p.Lys115Arg (c.344A>G) pathogenic?

CLDN15 p.Lys115Arg (c.344A>G) is classified Uncertain significance in CLDN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). AlphaMissense: likely benign (0.0695); Very rare (popmax 0.00178%, nfe).

How common is CLDN15 p.Lys115Arg (c.344A>G) in the general population?

CLDN15 p.Lys115Arg (c.344A>G) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about CLDN15 p.Lys115Arg (c.344A>G)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

CLDN15 p.Lys115Arg

c.344A>G · rs1486890021 · VCV2256445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.40	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 1.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 5,168 bp · p 0.00093 · regional, not allelic
Overall
CADD	15.66	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 0.00178% European (non-Finnish) · 21/1,179,830 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00143% 23/1,610,720 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,182
African / African-American	0.00133%	74,930
South Asian	0.0011%	91,082

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.Lys115Arg
Coding: c.344A>G
MANE Select: NM_014343
dbSNP: rs1486890021
Type: single nucleotide variant
Location: chr7:101234316 (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-lys115arg (accessed [today's date]).

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