HAP1 p.Pro521=
c.1563G>A · rs34453339 · VCV3037846
Benign
No assertion criteria
Classification
Benign
ClinVar
Review
No assertion criteria ☆☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Common
common (popmax 9.05%, afr) — too common for a highly-penetrant pathogenic allele
Conditions
1
HAP1-related disorder
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 -9.1 | GERP -2.2 |
| Overall | ||
| CADD | 0.215 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
9.05%
African / African-American · 6,790/74,988 alleles
Filtering AF
8.87%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 8.8%
Overall
1.36%
21,894/1,612,826 alleles · common
exomes 16,945/1,460,610 · genomes 4,949/152,216 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 9.05% | 11 |
| Ashkenazi Jewishnot grpmax-eligible | 4.57% | 22 |
| Middle Eastern | 1.82% | 55 |
| Remaining individualsnot grpmax-eligible | 1.6% | 62 |
| Admixed American | 1.36% | 73 |
| Amishnot grpmax-eligible | 0.987% | 101 |
| European (non-Finnish) | 0.965% | 104 |
| Finnishnot grpmax-eligible | 0.393% | 254 |
| South Asian | 0.187% | 536 |
| East Asian | 0.0134% | 7,480 |
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
- HAP1
- Protein
- p.Pro521=
- Coding
- c.1563G>A
- MANE Select
- NM_177977
- dbSNP
- rs34453339
- Type
- single nucleotide variant
- Location
- chr17:41724998 (GRCh38)
- Gene constraint
- LOEUF 1.31 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 64.28
Disease context
HAP1-related disorder
Similar variants
- HAP1 p.Pro521Leu Uncertain significance ★ ⚠ same residue
- HAP1 c.1201-4C>T Likely benign same condition
- HAP1 c.1201-7C>T Likely benign same condition
- HAP1 c.470-7C>G Likely benign same condition
- HAP1 p.Ala21= Likely benign same condition
- HAP1 p.Ala505Val Benign same condition
- HAP1 p.Arg116Trp Likely benign same condition
- HAP1 p.Asp339Asn Likely benign 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/hap1-p-pro521 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown