HERC2 p.Pro1325=
c.3975G>A · rs759567478 · VCV3234540
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0225%, mid)
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 -9 | |
| Overall | ||
| CADD | 2.53 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0225%
Middle Eastern · 1/4,452 alleles
Filtering AF
0.000444%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000211%
Overall
0.000869%
14/1,611,654 alleles · ultra-rare
exomes 12/1,459,448 · genomes 2/152,206 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0225% | 4,452 |
| African / African-American | 0.00267% | 37,414 |
| South Asian | 0.0022% | 45,492 |
| Admixed American | 0.00167% | 59,990 |
| European (non-Finnish) | 0.000678% | 147,461 |
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.Pro1325=
- Coding
- c.3975G>A
- MANE Select
- NM_004667
- dbSNP
- rs759567478
- Type
- single nucleotide variant
- Location
- chr15:28236991 (GRCh38)
- Gene constraint
- LOEUF 0.243 · pLI 1.00 (gnomAD)
Similar variants
- HERC2 p.Pro1325Leu Uncertain significance ★ ⚠ 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-pro1325 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown