Is PROK2 p.Ala28= (c.84C>G) pathogenic?

PROK2 p.Ala28= (c.84C>G) is classified Benign/Likely benign in PROK2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-03). Rare (popmax 0.307%, nfe); Associated with hypogonadotropic hypogonadism 4 with or without anosmia.

What condition is associated with PROK2 p.Ala28= (c.84C>G)?

PROK2 p.Ala28= (c.84C>G) is associated with hypogonadotropic hypogonadism 4 with or without anosmia (ClinVar).

How common is PROK2 p.Ala28= (c.84C>G) in the general population?

PROK2 p.Ala28= (c.84C>G) is rare (popmax 0.307%, nfe) (gnomAD).

PROK2 p.Ala28=

c.84C>G · rs372623686 · VCV378430

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.307%, nfe)

Conditions

hypogonadotropic hypogonadism 4 with or without anosmia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -3.5
Overall
CADD	3.384	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.307% European (non-Finnish) · 3,051/994,346 alleles

Filtering AF 0.298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.294%

Overall 0.266% 3,321/1,248,440 alleles · rare exomes 3,075/1,096,224 · genomes 246/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.307%	326
South Asian	0.293%	341
Remaining individualsnot grpmax-eligible	0.199%	503
Finnishnot grpmax-eligible	0.106%	945
Ashkenazi Jewishnot grpmax-eligible	0.0781%	1,280
African / African-American	0.0572%	1,748
Admixed American	0.0501%	1,994
Middle Eastern	0.0209%	4,778

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: PROK2
Protein: p.Ala28=
Coding: c.84C>G
MANE Select: NM_001126128
dbSNP: rs372623686
Type: single nucleotide variant
Location: chr3:71784969 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 69.22

Full PROK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 4 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROK2 p.Gly62Asp Uncertain significance ★★ ⚠ same condition
PROK2 p.Met1Thr Likely pathogenic ★ same condition
PROK2 c.-4C>A Conflicting classifications of pathogenicity ★ same condition
PROK2 p.Arg73Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
PROK2 p.Gly32Arg Uncertain significance ★ ⚠ same condition
PROK2 c.286-1G>A Likely pathogenic same condition
PROK2 p.Cys34Tyr Pathogenic same condition
PROK2 p.Ala24Pro Conflicting classifications of pathogenicity ⚠ 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/prok2-p-ala28 (accessed [today's date]).

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