Is CLDN19 p.Ala129Pro (c.385G>C) pathogenic?

CLDN19 p.Ala129Pro (c.385G>C) is classified Uncertain significance in CLDN19 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.944); Absent from gnomAD v4.1; Associated with renal hypomagnesemia 5 with ocular involvement.

What condition is associated with CLDN19 p.Ala129Pro (c.385G>C)?

CLDN19 p.Ala129Pro (c.385G>C) is associated with renal hypomagnesemia 5 with ocular involvement (ClinVar).

How common is CLDN19 p.Ala129Pro (c.385G>C) in the general population?

CLDN19 p.Ala129Pro (c.385G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLDN19 p.Ala129Pro (c.385G>C)?

AlphaMissense predicts likely pathogenic (score 0.944) — an in-silico prediction, not a clinical call.

CLDN19 p.Ala129Pro

Q: How is Primary hypomagnesemia with hypercalciuria and nephrocalcinosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.385G>C · VCV3583918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal hypomagnesemia 5 with ocular involvement

Computational evidence

Protein change
AlphaMissense	0.944	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -13.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 4,974 bp · p 0.0076 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLDN19
Protein: p.Ala129Pro
Coding: c.385G>C
MANE Select: NM_148960
Type: single nucleotide variant
Location: chr1:42738424 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.08

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

Disease context

renal hypomagnesemia 5 with ocular involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary hypomagnesemia with hypercalciuria and nephrocalcinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

CLDN19 p.Gly20Asp Pathogenic/Likely pathogenic ★★ same condition
CLDN19 p.Gly75Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLDN19 p.Leu90Arg Pathogenic/Likely pathogenic ★★ same condition
CLDN19 p.Pro28Leu Likely pathogenic ★★ same condition
CLDN19 c.-150C>T Uncertain significance ★★ same condition
CLDN19 p.Ala216Thr Uncertain significance ★★ ⚠ same condition
CLDN19 p.Ala218Thr Uncertain significance ★★ ⚠ same condition
CLDN19 p.Ala55Thr Uncertain significance ★★ ⚠ 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-ala129pro (accessed [today's date]).

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