Is PROKR2 p.Ala175= (c.525C>G) pathogenic?

PROKR2 p.Ala175= (c.525C>G) is classified Benign in PROKR2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-05-08). Common (popmax 12.5%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 3 with or without anosmia.

What condition is associated with PROKR2 p.Ala175= (c.525C>G)?

PROKR2 p.Ala175= (c.525C>G) is associated with hypogonadotropic hypogonadism 3 with or without anosmia (ClinVar).

PROKR2 p.Ala175=

Q: How common is PROKR2 p.Ala175= (c.525C>G) in the general population?

PROKR2 p.Ala175= (c.525C>G) is common (popmax 12.5%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.525C>G · rs3746683 · VCV138812

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 12.5%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

hypogonadotropic hypogonadism 3 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 -2.5	GERP -3.7
Overall
CADD	0.604	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.5% South Asian · 11,404/91,078 alleles

Filtering AF 12.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.2%

Overall 11.8% 190,877/1,614,038 alleles · common exomes 173,089/1,461,772 · genomes 17,788/152,266 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	17%	6
Ashkenazi Jewishnot grpmax-eligible	16.3%	6
South Asiangrpmax	12.5%	8
Remaining individualsnot grpmax-eligible	12.3%	8
European (non-Finnish)	11.9%	8
African / African-American	11.8%	8
Middle Eastern	10.7%	9
Admixed American	6.57%	15
Amishnot grpmax-eligible	4.93%	20
East Asian	3.9%	26

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala175=
Coding: c.525C>G
MANE Select: NM_144773
dbSNP: rs3746683
Type: single nucleotide variant
Location: chr20:5302670 (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.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-ala175 (accessed [today's date]).

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