Is PROKR2 p.Arg80Cys (c.238C>T) pathogenic?

PROKR2 p.Arg80Cys (c.238C>T) is classified Uncertain significance in PROKR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2082); Ultra-rare (popmax 0.0165%, mid); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Arg80Cys (c.238C>T)?

PROKR2 p.Arg80Cys (c.238C>T) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Arg80Cys (c.238C>T) in the general population?

PROKR2 p.Arg80Cys (c.238C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PROKR2 p.Arg80Cys (c.238C>T)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

PROKR2 p.Arg80Cys

c.238C>T · VCV3665849

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.2082	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0015% 22/1,461,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.00153%	65,555
African / African-American	0.00133%	75,040

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.Arg80Cys
Coding: c.238C>T
MANE Select: NM_144773
Type: single nucleotide variant
Location: chr20:5314132 (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.Arg80His 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-arg80cys (accessed [today's date]).

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