NEK1

Chr 4ARADDigenic recessive

NIMA related kinase 1

Also known as: ALS24, NY-REN-55, OFD2, SRPS2, SRPS2A, SRTD6

NCBI Gene: 4750 ENSG00000137601 OMIM: 604588

NEK1 encodes a serine/threonine kinase that functions in DNA damage repair, cell cycle regulation, and cilium assembly. Mutations cause short-rib thoracic dysplasia with or without polydactyly, orofaciodigital syndrome type II, and contribute to amyotrophic lateral sclerosis susceptibility, with inheritance patterns including autosomal recessive, autosomal dominant, and digenic recessive depending on the condition. The gene shows very low constraint against loss-of-function variants, consistent with its association with recessive developmental disorders affecting skeletal development and ciliary function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/AD/Digenic recessiveLOEUF 0.863 OMIM phenotypes

Clinical Summary— NEK1

🧬

Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis, susceptibility to, 24 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

111 unique Pathogenic / Likely Pathogenic· 458 VUS of 1057 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — NEK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.54

OE 0.68 (0.54–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.07Z-score

OE missense 0.88 (0.82–0.94)

542 obs / 616.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.54–0.86)

0≤0.351.4

Missense OE?0.88 (0.82–0.94)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 51 / 74.7Missense obs/exp: 542 / 616.8Syn Z: -0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNEK1-related short rib-polydactyly syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6939th %ile

GOF

0.6247th %ile

LOF

0.3647th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFIn totality, we detected 9 variants, comprising 3 novel heterozygous loss-of-function mutations and 6 rare missense variants (MAF < 0.1%) in NEK1.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 30093141 ↗

ClinVar Variant Classifications

1057 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54

Likely Pathogenic57

VUS458

Likely Benign302

Benign91

Conflicting70

Pathogenic

Likely Pathogenic

458

VUS

302

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	6	3	0	54
Likely Pathogenic	54	2	1	0	57
VUS	8	383	59	8	458
Likely Benign	0	15	167	120	302
Benign	0	2	83	6	91
Conflicting	—				70
Total	107	408	313	134	1,032

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap NEK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →