Is FXYD2 p.Phe38= (c.114C>T) pathogenic?

FXYD2 p.Phe38= (c.114C>T) is classified Likely benign in FXYD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-13). Ultra-rare (popmax 0.027%, afr); Associated with renal hypomagnesemia 2.

What condition is associated with FXYD2 p.Phe38= (c.114C>T)?

FXYD2 p.Phe38= (c.114C>T) is associated with renal hypomagnesemia 2 (ClinVar).

How common is FXYD2 p.Phe38= (c.114C>T) in the general population?

FXYD2 p.Phe38= (c.114C>T) is ultra-rare (popmax 0.027%, afr) (gnomAD).

FXYD2 p.Phe38=

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.114C>T · rs151172706 · VCV789041

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, afr)

Conditions

renal hypomagnesemia 2

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 1.4	GERP 0.26, phastCons 0.84
Overall
CADD	11.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.027% African / African-American · 20/74,088 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00211% 33/1,562,442 alleles · ultra-rare exomes 20/1,410,104 · genomes 13/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.027%	3,704
Remaining individualsnot grpmax-eligible	0.0099%	10,098
Admixed American	0.00771%	12,978
South Asian	0.00118%	84,790
European (non-Finnish)	0.000174%	576,216

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.Phe38=
Coding: c.114C>T
MANE Select: NM_001680
dbSNP: rs151172706
Type: single nucleotide variant
Location: chr11:117822431 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.04 · 4 PDB
Residue 38: an α-helix

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

Similar variants

FXYD2 p.Arg59Lys Uncertain significance ★★ ⚠ same condition
FXYD2 c.-10A>G Benign ★★ same condition
FXYD2 c.*1C>T Benign/Likely benign ★★ same condition
FXYD2 c.*6+6C>A Benign/Likely benign ★★ same condition
FXYD2 p.Ala37Asp Likely benign ★★ same condition
FXYD2 p.Ile61= Benign/Likely benign ★★ same condition
FXYD2 p.Pro66= Likely benign ★★ same condition
FXYD2 p.Val26Ile Benign/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/fxyd2-p-phe38 (accessed [today's date]).

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