Is PROKR2 p.Arg85Leu (c.254G>T) pathogenic?

PROKR2 p.Arg85Leu (c.254G>T) is classified Conflicting classifications of pathogenicity in PROKR2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-04). AlphaMissense: likely pathogenic (0.6784); Rare (popmax 0.103%, amr); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Arg85Leu (c.254G>T)?

PROKR2 p.Arg85Leu (c.254G>T) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Arg85Leu (c.254G>T) in the general population?

PROKR2 p.Arg85Leu (c.254G>T) is rare (popmax 0.103%, amr) (gnomAD).

What do computational predictors say about PROKR2 p.Arg85Leu (c.254G>T)?

AlphaMissense predicts likely pathogenic (score 0.6784) — an in-silico prediction, not a clinical call.

PROKR2 p.Arg85Leu

c.254G>T · rs74315418 · VCV338863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6784 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.6784	likely pathogenic
REVEL	0.745	pathogenic-leaning
SaProt	LLR -10.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% Admixed American · 62/60,026 alleles

Filtering AF 0.0826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.0329% 531/1,614,150 alleles · rare exomes 469/1,461,878 · genomes 62/152,272 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.103%	968
Remaining individualsnot grpmax-eligible	0.048%	2,084
European (non-Finnish)	0.0363%	2,757
African / African-American	0.0107%	9,379
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Finnishnot grpmax-eligible	0.00312%	32,011

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.Arg85Leu
Coding: c.254G>T
MANE Select: NM_144773
dbSNP: rs74315418
Type: single nucleotide variant
Location: chr20:5314116 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 85: a UniProt-annotated variant site (in hh3; phenotype consistent with normosmic idiopathic hypogonadotropic hypogonadism; decreased signaling activity); a UniProt-annotated variant site (in hh3; decreased signaling activity)

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.Arg85Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PROKR2 p.Arg85Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PROKR2 p.Arg85His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg85leu (accessed [today's date]).

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