NEK1

Chr 4

NIMA related kinase 1

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

NCBI Gene: 4750 ENSG00000137601 UniProt: Q96PY6

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 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 ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtShort-rib thoracic dysplasia 6 with or without polydactyly

UniProtAmyotrophic lateral sclerosis 24

UniProtOrofaciodigital syndrome 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · amyotrophic lateral sclerosis, susceptibility to, 24 · AD · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — NEK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in NEK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

1,534 rare PASS variants

Rare truncating (LoF)

1 in 380

297 rare PASS variants

Rare synonymous (reference)

1 in 82

550 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NEK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 66	1 in 400
South Asian	~43k	1 in 30	1 in 300
Remaining (unassigned)	~30k	1 in 44	1 in 370
European (Finnish)	~27k	1 in 170	1 in 810
Admixed American	~22k	1 in 53	1 in 300
African / African American	~21k	1 in 31	1 in 230
East Asian	~20k	1 in 36	1 in 280
Ashkenazi Jewish	~13k	1 in 300	1 in 1,000
Middle Eastern	~2,884	1 in 41	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 34 coding exons well covered in gnomAD exomes; exons 3, 5, 6, 7, 8 and 12 more marginal. Genomes: all 34.? see exons ↓