PROKR2 p.Arg85His
c.254G>A · rs74315418 · VCV3451
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1568 | likely benign |
|---|---|---|
| REVEL | 0.482 | indeterminate |
| SaProt | LLR -7.85 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Amishnot grpmax-eligible | 1.1% | 91 |
| European (non-Finnish)grpmax | 0.143% | 699 |
| Middle Eastern | 0.0986% | 1,014 |
| Remaining individualsnot grpmax-eligible | 0.0912% | 1,096 |
| Finnishnot grpmax-eligible | 0.0375% | 2,668 |
| South Asian | 0.0351% | 2,846 |
| Admixed American | 0.035% | 2,857 |
| African / African-American | 0.028% | 3,567 |
| East Asian | 0.00223% | 44,888 |
Amish 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.Arg85His
- Coding
- c.254G>A
- MANE Select
- NM_144773
- dbSNP
- rs74315418
- Type
- single nucleotide variant
- Location
- chr20:5314116 (GRCh38)
- Gene constraint
- LOEUF 1.492 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 78.50
- Residue 85
- a UniProt-annotated variant site (in hh3; phenotype consistent with normosmic idiopathic hypogonadotropic hypogonadism; decreased signaling activity); a UniProt-annotated variant site (in hh3; decreased signaling activity)
Disease context
Also linked: amenorrheahypogonadotropic hypogonadism 3 with or without anosmiaKallmann syndrome
Similar variants
- PROKR2 p.Arg85Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
- PROKR2 p.Arg85Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
- PROKR2 p.Arg85Leu Conflicting classifications of pathogenicity ★ ⚠ 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
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-arg85his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown