PROK2

Chr 3

prokineticin 2

Also known as: BV8, HH4, KAL4, MIT1, PK2

NCBI Gene: 60675 ENSG00000163421 UniProt: Q9HC23

This gene encodes prokineticin 2, a secreted protein that functions as an output molecule from the suprachiasmatic nucleus to transmit circadian behavioral rhythms and also contracts gastrointestinal smooth muscle. Mutations cause hypogonadotropic hypogonadism with or without anosmia (Kallmann syndrome), involving defective puberty and often absent sense of smell. The condition shows both autosomal dominant and autosomal recessive inheritance patterns.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHypogonadotropic hypogonadism 4 with or without anosmia

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hypogonadotropic hypogonadism 4 with or without anosmia · SD · ClinGen 2022

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.65

LOEUF

Mechanism· predicted

📖

GeneReview available — PROK2

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?

1.65LOEUF

pLI 0.014

Z-score 0.59

OE 0.69 (0.31–1.65)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.26Z-score

OE missense 1.10 (0.90–1.35)

64 obs / 58.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.69 (0.31–1.65)

0≤0.351.4

Missense OE?1.10 (0.90–1.35)

0≤0.61.4

Synonymous OE?0.69

0≤1.21.6

LoF obs/exp: 3 / 4.3Missense obs/exp: 64 / 58.4Syn Z: 1.05

Background carrier burden — how many people carry a rare variant somewhere in PROK2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

164 rare PASS variants

Rare truncating (LoF)

1 in 770

28 rare PASS variants

Rare synonymous (reference)

1 in 1,600

64 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PROK2; this gene does not show strong loss-of-function constraint by this measure. 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 540	1 in 650
South Asian	~43k	1 in 300	1 in 5,300
Remaining (unassigned)	~30k	1 in 330	1 in 1,200
European (Finnish)	~27k	1 in 1,200	1 in 2,800
Admixed American	~22k	1 in 260	1 in 2,200
African / African American	~21k	1 in 800	1 in 1,200
East Asian	~20k	1 in 480	1 in 2,100
Ashkenazi Jewish	~13k	1 in 250	none seen
Middle Eastern	~2,884	1 in 210	≈ 1 in 2,800

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓