Is PROKR2 p.Leu155= (c.465C>T) pathogenic?

PROKR2 p.Leu155= (c.465C>T) is classified Benign in PROKR2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-08). Common (popmax 48.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Leu155= (c.465C>T)?

PROKR2 p.Leu155= (c.465C>T) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

PROKR2 p.Leu155=

Q: How common is PROKR2 p.Leu155= (c.465C>T) in the general population?

PROKR2 p.Leu155= (c.465C>T) is common (popmax 48.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.465C>T · rs3746684 · VCV338859

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 48.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

hypogonadotropic hypogonadism 3 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 -6	GERP -3.7
Overall
CADD	0.059	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 48.8% East Asian · 21,880/44,842 alleles

Filtering AF 48.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 48%

Overall 39.4% 634,032/1,610,316 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	48.8%	2
African / African-American	45%	2
South Asian	43.4%	2
Middle Eastern	42.2%	2
Amishnot grpmax-eligible	41.2%	2
Admixed American	39.6%	3
Remaining individualsnot grpmax-eligible	39.3%	3
European (non-Finnish)	38.8%	3
Ashkenazi Jewishnot grpmax-eligible	33.8%	3
Finnishnot grpmax-eligible	33.2%	3

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: PROKR2
Protein: p.Leu155=
Coding: c.465C>T
MANE Select: NM_144773
dbSNP: rs3746684
Type: single nucleotide variant
Location: chr20:5302730 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50

Full PROKR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 3 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROKR2 p.Arg164Gln Likely pathogenic ★★ same condition
PROKR2 p.Glu231Lys Likely pathogenic ★★ ⚠ same condition
PROKR2 p.Tyr316Ter Likely pathogenic ★★ same condition
PROKR2 p.Ala103Val Uncertain significance ★★ ⚠ same condition
PROKR2 p.Ala129Thr Uncertain significance ★★ ⚠ same condition
PROKR2 p.Ala156Thr Uncertain significance ★★ same condition
PROKR2 p.Arg135Cys Uncertain significance ★★ ⚠ same condition
PROKR2 p.Arg248Trp 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/prokr2-p-leu155 (accessed [today's date]).

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