Is PROKR2 p.Leu91= (c.273C>T) pathogenic?

PROKR2 p.Leu91= (c.273C>T) is classified Conflicting classifications of pathogenicity in PROKR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-06-09). Very rare (popmax 0.0033%, nfe); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Leu91= (c.273C>T)?

PROKR2 p.Leu91= (c.273C>T) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Leu91= (c.273C>T) in the general population?

PROKR2 p.Leu91= (c.273C>T) is very rare (popmax 0.0033%, nfe) (gnomAD).

PROKR2 p.Leu91=

c.273C>T · rs759954578 · VCV898722

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 0.0033%, nfe)

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 1.4	GERP 1.1, phastCons 1
Overall
CADD	7.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% European (non-Finnish) · 39/1,180,054 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00266% 43/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0033%	30,258
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,473

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.Leu91=
Coding: c.273C>T
MANE Select: NM_144773
dbSNP: rs759954578
Type: single nucleotide variant
Location: chr20:5314097 (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.Leu91Phe Uncertain significance ★ same residue
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

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-leu91 (accessed [today's date]).

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