Is PROKR2 p.Pro290Ser (c.868C>T) pathogenic?

PROKR2 p.Pro290Ser (c.868C>T) is classified Conflicting classifications of pathogenicity in PROKR2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.8993); Ultra-rare (popmax 0.035%, amr); Associated with Male infertility with spermatogenesis disorder.

What condition is associated with PROKR2 p.Pro290Ser (c.868C>T)?

PROKR2 p.Pro290Ser (c.868C>T) is associated with Male infertility with spermatogenesis disorder, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism (ClinVar).

How common is PROKR2 p.Pro290Ser (c.868C>T) in the general population?

PROKR2 p.Pro290Ser (c.868C>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about PROKR2 p.Pro290Ser (c.868C>T)?

AlphaMissense predicts likely pathogenic (score 0.8993) — an in-silico prediction, not a clinical call.

PROKR2 p.Pro290Ser

c.868C>T · rs149992595 · VCV897086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.8993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Male infertility with spermatogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.8993	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -11.76	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	30.0	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 0.035% Admixed American · 21/60,028 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0237% 382/1,614,204 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0285%	3,512
African / African-American	0.00533%	18,762

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.Pro290Ser
Coding: c.868C>T
MANE Select: NM_144773
dbSNP: rs149992595
Type: single nucleotide variant
Location: chr20:5302327 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 290: a UniProt-annotated variant site (in hh3; phenotype consistent with kallmann syndrome; signaling activity is impaired; impaired cell surface-targeting)

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

Disease context

Male infertility with spermatogenesis disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypogonadotropic hypogonadism 3 with or without anosmia hypogonadotropic hypogonadism

Similar variants

PROKR2 p.Pro290= 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
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-pro290ser (accessed [today's date]).

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