HERC2 p.Pro594=
c.1782G>A · rs147892890 · VCV2645079
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0733%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -7.4 | |
| Overall | ||
| CADD | 0.113 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0733%
African / African-American · 55/75,062 alleles
Filtering AF
0.0577%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0522%
Overall
0.00719%
116/1,614,214 alleles · ultra-rare
exomes 86/1,461,886 · genomes 30/152,328 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0733% | 1,365 |
| Remaining individualsnot grpmax-eligible | 0.0176% | 5,683 |
| European (non-Finnish) | 0.00407% | 24,584 |
| Finnishnot grpmax-eligible | 0.00156% | 64,042 |
| South Asian | 0.0011% | 91,086 |
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
- HERC2
- Protein
- p.Pro594=
- Coding
- c.1782G>A
- MANE Select
- NM_004667
- dbSNP
- rs147892890
- Type
- single nucleotide variant
- Location
- chr15:28265706 (GRCh38)
- Gene constraint
- LOEUF 0.243 · pLI 1.00 (gnomAD)
- Residue 594
- a UniProt-annotated variant site (in mrt38; decreased protein abundance in transfected cells); a β-strand
Similar variants
- HERC2 p.Pro594Leu Pathogenic ★ same residue
- HERC2 c.4352-1G>A Likely pathogenic ★★ same type
- HERC2 p.Arg1376Ter Pathogenic/Likely pathogenic ★★ same type
- HERC2 c.12803-7C>A Uncertain significance ★★ same type
- HERC2 c.8451+8C>A Uncertain significance ★★ same type
- HERC2 p.Ala1253Thr Uncertain significance ★★ same type
- HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same type
- HERC2 p.Ala200Val Uncertain significance ★★ ⚠ 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/herc2-p-pro594 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown