Is FXYD2 p.Pro18Leu (c.53C>T) pathogenic?

FXYD2 p.Pro18Leu (c.53C>T) is classified Uncertain significance in FXYD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-28). AlphaMissense: ambiguous (0.4498); Very rare (popmax 0.00223%, eas); Associated with renal hypomagnesemia 2.

What condition is associated with FXYD2 p.Pro18Leu (c.53C>T)?

FXYD2 p.Pro18Leu (c.53C>T) is associated with renal hypomagnesemia 2 (ClinVar).

How common is FXYD2 p.Pro18Leu (c.53C>T) in the general population?

FXYD2 p.Pro18Leu (c.53C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FXYD2 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.4498) — an in-silico prediction, not a clinical call.

FXYD2 p.Pro18Leu

Q: How is Autosomal dominant primary hypomagnesemia with hypocalciuria inherited?

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

c.53C>T · rs763425417 · VCV2414831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

renal hypomagnesemia 2

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.4498	ambiguous
REVEL	0.426	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,003 bp · p 0.98 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,772 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000931% 15/1,610,632 alleles · very rare exomes 12/1,458,510 · genomes 3/152,122 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,772
South Asian	0.00222%	44,968
Remaining individualsnot grpmax-eligible	0.0016%	62,336
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000848%	117,920

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: FXYD2
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_001680
dbSNP: rs763425417
Type: single nucleotide variant
Location: chr11:117822690 (GRCh38)

Full FXYD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

renal hypomagnesemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant primary hypomagnesemia with hypocalciuria (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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/fxyd2-p-pro18leu (accessed [today's date]).

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