Is PROKR2 p.Val158Ile (c.472G>A) pathogenic?

PROKR2 p.Val158Ile (c.472G>A) is classified Conflicting classifications of pathogenicity in PROKR2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.1097); Ultra-rare (popmax 0.0657%, mid); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Val158Ile (c.472G>A)?

PROKR2 p.Val158Ile (c.472G>A) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Val158Ile (c.472G>A) in the general population?

PROKR2 p.Val158Ile (c.472G>A) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about PROKR2 p.Val158Ile (c.472G>A)?

AlphaMissense predicts likely benign (score 0.1097) — an in-silico prediction, not a clinical call.

PROKR2 p.Val158Ile

c.472G>A · rs368732206 · VCV2741590

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.1097	likely benign
REVEL	0.667	pathogenic-leaning
SaProt	LLR -6.48	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	23.6	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0116% 187/1,613,492 alleles · ultra-rare exomes 175/1,461,380 · genomes 12/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
South Asian	0.0549%	1,822
Remaining individualsnot grpmax-eligible	0.0256%	3,904
African / African-American	0.0107%	9,358
European (non-Finnish)	0.0089%	11,235
Admixed American	0.00667%	15,000

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.Val158Ile
Coding: c.472G>A
MANE Select: NM_144773
dbSNP: rs368732206
Type: single nucleotide variant
Location: chr20:5302723 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 158: a UniProt-annotated variant site (in hh3; phenotype consistent with kallmann syndrome)

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.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
PROKR2 p.Arg248Trp 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-val158ile (accessed [today's date]).

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