Is CLDN19 p.Pro192Arg (c.575C>G) pathogenic?

CLDN19 p.Pro192Arg (c.575C>G) is classified Uncertain significance in CLDN19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.00043%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLDN19 p.Pro192Arg (c.575C>G)?

CLDN19 p.Pro192Arg (c.575C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLDN19 p.Pro192Arg (c.575C>G) in the general population?

CLDN19 p.Pro192Arg (c.575C>G) is very rare (popmax 0.00043%, nfe) (gnomAD).

What do computational predictors say about CLDN19 p.Pro192Arg (c.575C>G)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

CLDN19 p.Pro192Arg

c.575C>G · VCV4615948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00043%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.16	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 3.2	GERP -0.51, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 4,974 bp · p 0.0076 · regional, not allelic
Overall
CADD	12.23	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 0.00043% European (non-Finnish) · 5/1,162,446 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000317% 5/1,578,948 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: CLDN19
Protein: p.Pro192Arg
Coding: c.575C>G
MANE Select: NM_148960
Type: single nucleotide variant
Location: chr1:42735929 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.08
Residue 192: the 'disordered' region

Full CLDN19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLDN19 p.Ala55Thr Uncertain significance ★★ ⚠ same condition
CLDN19 p.Arg106Trp Uncertain significance ★★ ⚠ same condition
CLDN19 p.Arg208Gln Uncertain significance ★★ ⚠ same condition
CLDN19 p.Leu50Ile Uncertain significance ★★ ⚠ same condition
CLDN19 p.Leu50Phe Uncertain significance ★★ ⚠ same condition
CLDN19 p.Pro112Leu Uncertain significance ★★ ⚠ same condition
CLDN19 p.Val224Glu Uncertain significance ★★ ⚠ same condition
CLDN19 p.Gly178= Likely benign ★★ same condition

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/cldn19-p-pro192arg (accessed [today's date]).

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