FXYD2

protein-coding

FXYD domain containing ion transport regulator 2

Gene summary

This gene encodes a member of the FXYD family of transmembrane proteins. This particular protein encodes the sodium/potassium-transporting ATPase subunit gamma. Mutations in this gene have been associated with Renal Hypomagnesemia-2. Alternatively spliced transcript variants have been described. Read-through transcripts have been observed between this locus and the upstream FXYD domain-containing ion transport regulator 6 (FXYD6, GeneID 53826) locus.[provided by RefSeq, Feb 2011]

Previous symbols:

ATP1G1
HOMG2

MANE transcript

NM_001680.5

Inheritance

ClinVar variants

P:1U:22B:20

Top phenotype

Hypomagnesemia 2, renal

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr11:117,800,844-117,828,698

External References & Databases

Ensembl (ENSG00000137731)

Transcript & Mutation Effects

hg38 • Region Span ~27.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal hypomagnesemia 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007937

Submitter: PanelApp Australia

renal hypomagnesemia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007937

Submitter: Labcorp Genetics (formerly Invitae)

renal hypomagnesemia 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007937

Submitter: ClinGen

FXYD2 was first reported in relation to autosomal dominant renal hypomagnesemia 2 in 2000 (Meij et al. 2000, PMID: 11062458). The gene is associated with low magnesium levels due to a loss of kidney magnesium, as well as hypokalemia, hypocalciuria, and renal failure. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no relevant differences in molecular mechanism, inheritance pattern or phenotypic variability (there is only one disease assertion for this gene). Therefore, no pre-curation was needed. One variant (the missense variant Gly41Arg) has been reported in 18 probands from one family in 2 publications (PMIDs: 25765846, 11062458) included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by experimental evidence (biochemical functional evidence, expression level data, functional alteration evidence, and a mouse model; PMIDs: 18787637, 18448590, 18448590, 15755730). In summary, FXYD2 is moderately associated with autosomal dominant renal hypomagnesemia 2. The disease is only associated with one variant in the gene, but there is case-level data (including lots of segregation) and various experimental evidence to support the relationship. Thus, a moderate classification, which was reached based on the point system (7.0 points were reached), felt appropriate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Tubulopathy GCEP on 6/29/2023 (SOP Version 9). It was reevaluated on 12/3/2025 (SOP Version 11). As a result of this reevaluation, the classification did not change. There was no new scorable evidence, despite a new case (PMID: 40428357) that was evaluated but not counted due to lack of phenotypic specificity.

renal hypomagnesemia 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007937

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypomagnesemia 2, renalAD

Manifestation: Renal

Intervention: Renal

Rationale: Surveillance for and treatment of electrolyte abnormalities can be beneficial (eg, to avoid sequelae such as pseudogout, as has been described in affected individuals)

Refs: 3298795; 11062458

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FXYD2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 57

Renal hypomagnesemia 2Total: 28

not specifiedTotal: 15

FXYD2-related disorderTotal: 11

Inborn genetic diseasesTotal: 4

FXYD6-FXYD2-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001680.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	12 clinvar	2 clinvar	16
missense	1 clinvar		18 clinvar	5 clinvar		24
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar	1 clinvar		2
Total	1	0	22	18	2	43

Highest pathogenic variant AF is 7.1018286e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001680.5	RefSeq	NP_001671.2	5	MANE Select
ENST00000292079.7	Ensembl	ENSP00000292079.2	5	MANE Select
NM_021603.4	RefSeq	NP_067614.1	5	Standard
ENST00000260287.2	Ensembl	ENSP00000260287.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Thyroid hormone synthesis - Homo sapiens (human)
Protein digestion and absorption - Homo sapiens (human)
Bile secretion - Homo sapiens (human)
Carbohydrate digestion and absorption - Homo sapiens (human)

Biological Process

establishment or maintenance of transmembrane electrochemical gradient
sodium ion export across plasma membrane
ATP hydrolysis coupled transmembrane transport
potassium ion import across plasma membrane
regulation of sodium ion transmembrane transporter activity

Molecular Function

transporter activity
sodium:potassium-exchanging ATPase activity
sodium channel regulator activity
ion channel regulator activity

Cellular Component

plasma membrane
sodium:potassium-exchanging ATPase complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292079
Coding exons: 5
Length: 27855
Individuals with no LoFs: 125469
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125471
p: 0.00000797

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.156	49	46.0	1.06	0.00000312	426
Missense (PolyPhen)		20	17.963	1.1134		185
Synonymous	-0.977	23	17.8	1.29	0.00000130	114
Loss of Function	1.30	2	5.21	0.384	2.21e-7	67

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in forming the receptor site for cardiac glycoside binding or may modulate the transport function of the sodium ATPase.;

Intolerance Scores

LoFtool: 0.281
RVIS EVS: 0.19
RVIS percentile EVS: 66.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.000434

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium