HOOK1

Chr 1

hook microtubule tethering protein 1

Also known as: HK1

NCBI Gene: 51361 ENSG00000134709 UniProt: Q9UJC3

The HOOK1 protein is a component of the FTS/Hook/FHIP complex that promotes vesicle trafficking and fusion by linking endocytic membrane trafficking to the microtubule cytoskeleton. Mutations cause autosomal recessive spermatogenic failure, leading to male infertility due to defects in spermatid differentiation and flagellar positioning. The gene is not highly constrained against loss-of-function variants, consistent with its specialized role in male reproductive function.

GeneReviews ResearchSummary from RefSeq, UniProt

This gene encodes a member of the hook family of coiled-coil proteins, which bind to microtubules and organelles through their N- and C-terminal domains, respectively. The encoded protein localizes to discrete punctuate subcellular structures, and interacts with several members of the Rab GTPase family involved in endocytosis. It is thought to link endocytic membrane trafficking to the microtubule cytoskeleton. Several alternatively spliced transcript variants have been identified, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

DNmechanismLOEUF 0.62

Clinical Summary— HOOK1

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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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ClinVar Variants

95 VUS of 123 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HOOK1

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?

0.62LOEUF

pLI 0.000

Z-score 3.66

OE 0.43 (0.31–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.85Z-score

OE missense 0.87 (0.80–0.96)

318 obs / 363.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.31–0.62)

0≤0.351.4

Missense OE?0.87 (0.80–0.96)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 21 / 48.5Missense obs/exp: 318 / 363.5Syn Z: 0.51

This gene — mechanism propensity

0.7326th %ile

GOF

0.5955th %ile

LOF

0.3260th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

123 submitted variants in ClinVar

ClinVar

Classification Summary

VUS95

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	95	0	95
Likely Benign	3	2	5
Benign	0	0	0
Total	98	2	100

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap HOOK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →