HOOK3

Chr 8

hook microtubule tethering protein 3

Also known as: HK3

NCBI Gene: 84376 ENSG00000168172 UniProt: Q86VS8 OMIM: 607825

HOOK3 encodes an adapter protein that links the dynein motor complex to cellular cargos and activates dynein processivity for microtubule-based transport, while also participating in vesicle trafficking and Golgi complex organization. Mutations cause autosomal recessive progressive familial intrahepatic cholestasis with neurologic features including intellectual disability and cerebellar atrophy. This gene is highly constrained against loss-of-function variants, indicating that functional HOOK3 protein is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, UniProt

Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.15

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 6.16

OE 0.06 (0.03–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.36Z-score

OE missense 0.65 (0.58–0.72)

230 obs / 354.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.15)

0≤0.351.4

Missense OE?0.65 (0.58–0.72)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 3 / 50.0Missense obs/exp: 230 / 354.9Syn Z: 1.04

Background carrier burden — how many people carry a rare variant somewhere in HOOK3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

680 rare PASS variants

Rare truncating (LoF)

1 in 2,700

74 rare PASS variants

Rare synonymous (reference)

1 in 170

288 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HOOK3. 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 130	1 in 2,400
South Asian	~43k	1 in 100	1 in 3,000
Remaining (unassigned)	~30k	1 in 180	1 in 4,900
European (Finnish)	~27k	1 in 530	1 in 1,000
Admixed American	~22k	1 in 150	≈ 1 in 5,400
African / African American	~21k	1 in 140	1 in 2,700
East Asian	~20k	1 in 180	≈ 1 in 6,100
Ashkenazi Jewish	~13k	1 in 490	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 570	≈ 1 in 1,400

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): 7 of 22 coding exons well covered in gnomAD exomes; exon 19 poorly covered; exons 1, 2, 3, 4, 5 and 9 more marginal. Genomes: all 22.? see exons ↓