PROC p.Pro289His
c.866C>A · VCV4540674
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely benign
0.2306 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
1/3 damaging
AlphaMissense, REVEL, SaProt
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2306 | likely benign |
|---|---|---|
| REVEL | 0.782 | moderately pathogenic-leaning |
| SaProt | LLR -9.38 | 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 | phastCons 1 |
| Regional constraint | o/e 0.84 | unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic |
| Overall | ||
| CADD | 25.9 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- PROC
- Protein
- p.Pro289His
- Coding
- c.866C>A
- MANE Select
- NM_000312
- Type
- single nucleotide variant
- Location
- chr2:127428426 (GRCh38)
- Gene constraint
- LOEUF 0.894 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.35 · 12 PDB
- Residue 289
- a UniProt-annotated variant site (in thph4); the peptidase s1 domain
Similar variants
- PROC p.Pro289Leu Pathogenic ⚠ same residue
- PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
- PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
- PROC p.Arg199Ter Pathogenic ★★ same type
- PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
- PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
- PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
- PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
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/proc-p-pro289his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown