NKAIN4

Chr 20

sodium/potassium transporting ATPase interacting 4

Also known as: C20orf58, FAM77A, bA261N11.2

NCBI Gene: 128414 ENSG00000101198 UniProt: Q8IVV8 OMIM: 612873

The protein interacts with the beta subunit of Na,K-ATPase and is part of a family with similarity to Drosophila Nkain proteins. Mutations cause autosomal recessive neurodevelopmental disorder with seizures, microcephaly, and brain atrophy. The gene shows low constraint to loss-of-function variation, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq

NKAIN4 is a member of a family of mammalian proteins (see NKAIN1; MIM 612871) with similarity to Drosophila Nkain and interacts with the beta subunit of Na,K-ATPase (ATP1B1; MIM 182330) (Gorokhova et al., 2007 [PubMed 17606467]).[supplied by OMIM, Jun 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.99

Clinical Summary— NKAIN4

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

42 VUS of 52 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.007

Z-score 1.60

OE 0.47 (0.24–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.06Z-score

OE missense 1.02 (0.87–1.19)

110 obs / 108.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.47 (0.24–0.99)

0≤0.351.4

Missense OE?1.02 (0.87–1.19)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 5 / 10.6Missense obs/exp: 110 / 108.2Syn Z: 0.69

This gene — mechanism propensity

0.79top 25%

GOF

0.83top 10%

LOF

0.1994th %ile

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

GOFprediction above median

DNprediction 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.

ClinVar Variant Classifications

52 submitted variants in ClinVar

ClinVar

Classification Summary

VUS42

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	42	42
Likely Benign	5	5
Benign	0	0
Total	47	47

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

48 pathogenic / likely-pathogenic (of 73) ClinVar copy-number / structural variants overlap NKAIN4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →