Is GNRH1 c.237+8A>C pathogenic?

GNRH1 c.237+8A>C is classified Conflicting classifications of pathogenicity in GNRH1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-28). Very rare (popmax 0.00416%, nfe); Associated with hypogonadotropic hypogonadism 12 with or without anosmia.

What condition is associated with GNRH1 c.237+8A>C?

GNRH1 c.237+8A>C is associated with hypogonadotropic hypogonadism 12 with or without anosmia (ClinVar).

How common is GNRH1 c.237+8A>C in the general population?

GNRH1 c.237+8A>C is very rare (popmax 0.00416%, nfe) (gnomAD).

GNRH1 c.237+8A>C

rs751932727 · VCV362650

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00416%, nfe)

Conditions

hypogonadotropic hypogonadism 12 with or without anosmia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.98	GERP -3.9
Overall
CADD	0.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00416% European (non-Finnish) · 43/1,034,324 alleles

Filtering AF 0.00313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.00296% 43/1,452,398 alleles · very rare exomes 37/1,300,434 · genomes 6/151,964 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GNRH1
Coding: c.237+8A>C
MANE Select: NM_001083111
dbSNP: rs751932727
Type: single nucleotide variant
Location: chr8:25421565 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI 0.33 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.63 · 2 PDB

Full GNRH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 12 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNRH1 c.-2+388T>C Likely benign ★★ same condition
GNRH1 p.Phe61= Benign ★★ same condition
GNRH1 p.Trp16Ser Benign ★★ same condition
GNRH1 c.238-12T>C Uncertain significance ★ same condition
GNRH1 c.-1-110A>G Uncertain significance ★ same condition
GNRH1 c.-1-140G>A Uncertain significance ★ same condition
GNRH1 c.-1198G>A Uncertain significance ★ same condition
GNRH1 c.-1316C>T Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gnrh1-c-237-plus-8a-c (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown