Is GNRH1 p.Phe61= (c.183C>T) pathogenic?

GNRH1 p.Phe61= (c.183C>T) is classified Benign in GNRH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-30). Low-frequency (popmax 3.67%, afr); Associated with hypogonadotropic hypogonadism 12 with or without anosmia.

What condition is associated with GNRH1 p.Phe61= (c.183C>T)?

GNRH1 p.Phe61= (c.183C>T) is associated with hypogonadotropic hypogonadism 12 with or without anosmia (ClinVar).

How common is GNRH1 p.Phe61= (c.183C>T) in the general population?

GNRH1 p.Phe61= (c.183C>T) is low-frequency (popmax 3.67%, afr) (gnomAD).

GNRH1 p.Phe61=

c.183C>T · rs6186 · VCV788272

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.67%, afr)

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
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.9
Overall
CADD	0.091	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.67% African / African-American · 2,745/74,780 alleles

Filtering AF 3.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.51%

Overall 0.643% 10,326/1,606,116 alleles · low-frequency exomes 8,366/1,453,920 · genomes 1,960/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.67%	27
Remaining individualsnot grpmax-eligible	0.58%	172
European (non-Finnish)	0.571%	175
Admixed American	0.524%	191
Finnishnot grpmax-eligible	0.27%	370
Middle Eastern	0.109%	915
South Asian	0.0209%	4,780
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,922
East Asian	0.00223%	44,844

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
Protein: p.Phe61=
Coding: c.183C>T
MANE Select: NM_001083111
dbSNP: rs6186
Type: single nucleotide variant
Location: chr8:25421627 (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.Trp16Ser Benign ★★ same condition
GNRH1 c.237+8A>C Conflicting classifications of pathogenicity ★ 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-p-phe61 (accessed [today's date]).

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