Is PROKR2 p.Arg80His (c.239G>A) pathogenic?

PROKR2 p.Arg80His (c.239G>A) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1378); Very rare (popmax 0.00534%, afr); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Arg80His (c.239G>A)?

PROKR2 p.Arg80His (c.239G>A) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Arg80His (c.239G>A) in the general population?

PROKR2 p.Arg80His (c.239G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PROKR2 p.Arg80His (c.239G>A)?

AlphaMissense predicts likely benign (score 0.1378) — an in-silico prediction, not a clinical call.

PROKR2 p.Arg80His

c.239G>A · rs768671137 · VCV3241986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.1378	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,886 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,722
Admixed American	0.005%	20,004
South Asian	0.00329%	30,361
European (non-Finnish)	0.00119%	84,286

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.Arg80His
Coding: c.239G>A
MANE Select: NM_144773
dbSNP: rs768671137
Type: single nucleotide variant
Location: chr20:5314131 (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.Arg80Cys Uncertain significance ★★ ⚠ same residue
PROKR2 p.Arg80Leu Uncertain significance ★ same residue
PROKR2 p.Arg80= Likely benign ★ 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-arg80his (accessed [today's date]).

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