NEK1

Chr 4ARADDigenic recessive

NIMA related kinase 1

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

NCBI Gene: 4750ENSG00000137601UniProt: Q96PY6

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]

Primary Disease Associations & Inheritance

?Orofaciodigital syndrome IIMIM #252100
AR
{Amyotrophic lateral sclerosis, susceptibility to, 24}MIM #617892
AD
Short-rib thoracic dysplasia 6 with or without polydactylyMIM #263520
ARDigenic recessive
390
ClinVar variants
69
Pathogenic / LP
0.00
pLI score
0
Active trials
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
69 Pathogenic / Likely Pathogenic· 190 VUS of 390 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.86LOEUF
pLI 0.000
Z-score 2.54
OE 0.68 (0.54–0.86)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.07Z-score
OE missense 0.88 (0.82–0.94)
542 obs / 616.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.68 (0.54–0.86)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.82–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 51 / 74.7Missense obs/exp: 542 / 616.8Syn Z: -0.14

ClinVar Variant Classifications

390 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic27
VUS190
Likely Benign82
Benign20
Conflicting29
42
Pathogenic
27
Likely Pathogenic
190
VUS
82
Likely Benign
20
Benign
29
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
30
0
42
Likely Pathogenic
18
1
8
0
27
VUS
1
158
28
3
190
Likely Benign
0
4
44
34
82
Benign
0
2
13
5
20
Conflicting
—29
Total3016612342390

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

View in ClinVar →

Protein Context — Lollipop Plot

NEK1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NEK1-related short rib-polydactyly syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Orofaciodigital syndrome II

MIM #252100

Molecular basis of disorder known

Autosomal recessive

{Amyotrophic lateral sclerosis, susceptibility to, 24}

MIM #617892

Molecular basis of disorder known

Autosomal dominant

Short-rib thoracic dysplasia 6 with or without polydactyly

MIM #263520

Molecular basis of disorder known

Autosomal recessiveDigenic recessive
📖
GeneReview available — NEK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
Chia R et al.·Lancet Neurol
2018Review
Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.
Chen YP et al.·J Med Genet
2022Cohort
Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis.
Noh MY et al.·Mol Neurodegener
2025Functional
Genetic variability in sporadic amyotrophic lateral sclerosis.
Van Daele SH et al.·Brain
2023
ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.
Zelina P et al.·Acta Neuropathol Commun
2024
NEK1 haploinsufficiency worsens DNA damage, but not defective ciliogenesis, in C9ORF72 patient-derived iPSC-motoneurons.
Santangelo S et al.·Hum Mol Genet
2024
Genetic and clinical characteristics of ALS patients with NEK1 gene variants.
Jiang Q et al.·Neurobiol Aging
2023Cohort
A novel NEK1 variant disturbs the interaction between the C-terminal fragment of NEK1 and the VDAC1 channel, causing lethal short-rib polydactyly syndrome.
Gruca-Stryjak K et al.·Bone
2025
Exploring NEK1 genetic variability in Italian amyotrophic lateral sclerosis patients.
Pensato V et al.·J Neurol
2025Cohort
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools