GNRH1

Chr 8AR

gonadotropin releasing hormone 1

Also known as: GNRH, GRH, LHRH, LNRH

NCBI Gene: 2796 ENSG00000147437 UniProt: P01148 OMIM: 152760

This gene encodes gonadotropin-releasing hormone, which stimulates the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gland. Mutations cause autosomal recessive hypogonadotropic hypogonadism with or without anosmia, affecting reproductive development and function. The gene shows relatively low constraint to loss-of-function variants (pLI 0.15).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) family of peptides. Alternative splicing results in multiple transcript variants, at least one of which is secreted and then cleaved to generate gonadoliberin-1 and GnRH-associated peptide 1. Gonadoliberin-1 stimulates the release of luteinizing and follicle stimulating hormones, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism. [provided by RefSeq, Nov 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Hypogonadotropic hypogonadism 12 with or without anosmiaMIM #614841

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

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.05

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — GNRH1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.151

Z-score 1.51

OE 0.33 (0.14–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.94 (0.74–1.19)

49 obs / 52.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.14–1.05)

0≤0.351.4

Missense OE?0.94 (0.74–1.19)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 2 / 6.0Missense obs/exp: 49 / 52.3Syn Z: 0.05

Background carrier burden — how many people carry a rare variant somewhere in GNRH1?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 370

126 rare PASS variants

Rare truncating (LoF)

1 in 4,900

29 rare PASS variants

Rare synonymous (reference)

1 in 540

47 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GNRH1. 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 740	1 in 5,300
South Asian	~43k	1 in 750	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 590	1 in 4,200
European (Finnish)	~27k	1 in 550	none seen
Admixed American	~22k	1 in 270	none seen
African / African American	~21k	1 in 310	1 in 3,200
East Asian	~20k	1 in 330	none seen
Ashkenazi Jewish	~13k	1 in 440	none seen
Middle Eastern	~2,882	≈ 1 in 660	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): 1 of 3 coding exons well covered in gnomAD exomes; exons 3, 4 marginal. Genomes: all 3.? see exons ↓