FXYD4

Chr 10

FXYD domain containing ion transport regulator 4

Also known as: CHIF

NCBI Gene: 53828 ENSG00000150201 UniProt: P59646

This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. FXYD4, originally named CHIF for channel-inducing factor, has been shown to modulate the properties of the Na,K-ATPase, as has FXYD2, also known as the gamma subunit of the Na,K-ATPase, and FXYD7. Transmembrane topology has been established for FXYD4 and two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. Alternatively spliced transcript variants encoding the same protein have been found.[provided by RefSeq, May 2010]

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Active trials

Pubs (1 yr)

P/LP submissions

—

P/LP missense

1.49

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— FXYD4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.49LOEUF

pLI 0.000

Z-score 0.61

OE 0.77 (0.42–1.49)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.30Z-score

OE missense 1.13 (0.90–1.42)

52 obs / 46.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.77 (0.42–1.49)

0≤0.351.4

Missense OE1.13 (0.90–1.42)

0≤0.61.4

Synonymous OE1.08

0≤1.21.6

LoF obs/exp: 6 / 7.8Missense obs/exp: 52 / 46.2Syn Z: -0.27

0.81top 10%

GOF

0.81top 10%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.