Is CLDN19 p.Ser56= (c.168C>G) pathogenic?

CLDN19 p.Ser56= (c.168C>G) is classified Conflicting classifications of pathogenicity in CLDN19 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-08). Very rare (popmax 0.00619%, nfe); Associated with renal hypomagnesemia 5 with ocular involvement.

What condition is associated with CLDN19 p.Ser56= (c.168C>G)?

CLDN19 p.Ser56= (c.168C>G) is associated with renal hypomagnesemia 5 with ocular involvement (ClinVar).

How common is CLDN19 p.Ser56= (c.168C>G) in the general population?

CLDN19 p.Ser56= (c.168C>G) is very rare (popmax 0.00619%, nfe) (gnomAD).

CLDN19 p.Ser56=

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.168C>G · rs907045006 · VCV297344

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

Conditions

renal hypomagnesemia 5 with ocular involvement

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -4.2, phastCons 0.81
Overall
CADD	8.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00619% European (non-Finnish) · 73/1,179,760 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00463%

Overall 0.00465% 75/1,612,884 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00619%	16,161
Remaining individualsnot grpmax-eligible	0.0016%	62,460
African / African-American	0.00133%	74,928

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.Ser56=
Coding: c.168C>G
MANE Select: NM_148960
dbSNP: rs907045006
Type: single nucleotide variant
Location: chr1:42739896 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.08
Residue 56: a disulfide bond

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-ser56 (accessed [today's date]).

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