Is PROKR2 p.Val331Met (c.991G>A) pathogenic?

PROKR2 p.Val331Met (c.991G>A) is classified Benign/Likely benign in PROKR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-12). AlphaMissense: likely benign (0.0754); Low-frequency (popmax 2.83%, sas); Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Val331Met (c.991G>A)?

PROKR2 p.Val331Met (c.991G>A) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

How common is PROKR2 p.Val331Met (c.991G>A) in the general population?

PROKR2 p.Val331Met (c.991G>A) is low-frequency (popmax 2.83%, sas) (gnomAD).

What do computational predictors say about PROKR2 p.Val331Met (c.991G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

PROKR2 p.Val331Met

c.991G>A · rs117106081 · VCV338854

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.83%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 3 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -1.9, phastCons 0.79
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	15.9	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 2.83% South Asian · 2,580/91,076 alleles

Filtering AF 2.74% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.7%

Overall 0.262% 4,231/1,614,198 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.83%	35
East Asian	2.55%	39
Remaining individualsnot grpmax-eligible	0.39%	256
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0204%	4,896
African / African-American	0.0173%	5,773
Admixed American	0.01%	10,005

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.Val331Met
Coding: c.991G>A
MANE Select: NM_144773
dbSNP: rs117106081
Type: single nucleotide variant
Location: chr20:5302204 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 331: a UniProt-annotated variant site (in hh3; likely benign)

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-val331met (accessed [today's date]).

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