HPS4 p.Pro247=
c.741T>C · rs35126034 · VCV723870
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
rare (popmax 0.907%, 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 -1.5 | GERP -0.74 |
| Overall | ||
| CADD | 6.547 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.907%
African / African-American · 681/75,046 alleles
Filtering AF
0.851%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.829%
Overall
0.0473%
764/1,614,142 alleles · rare
exomes 379/1,461,818 · genomes 385/152,324 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.907% | 110 |
| Remaining individualsnot grpmax-eligible | 0.0528% | 1,894 |
| Middle Eastern | 0.0495% | 2,021 |
| Admixed American | 0.0433% | 2,309 |
| South Asian | 0.00439% | 22,771 |
| European (non-Finnish) | 0.00144% | 69,411 |
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
- HPS4
- Protein
- p.Pro247=
- Coding
- c.741T>C
- MANE Select
- NM_022081
- dbSNP
- rs35126034
- Type
- single nucleotide variant
- Location
- chr22:26465517 (GRCh38)
- Gene constraint
- LOEUF 0.794 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 62.83 · 1 PDB
Similar variants
- HPS4 c.133-2A>G Likely pathogenic ★★ same type
- HPS4 c.706+1G>A Pathogenic/Likely pathogenic ★★ same type
- HPS4 p.Arg217Ter Pathogenic/Likely pathogenic ★★ same type
- HPS4 p.Gln378Ter Pathogenic/Likely pathogenic ★★ same type
- HPS4 p.Gln50Ter Likely pathogenic ★★ same type
- HPS4 p.Gln516Ter Pathogenic/Likely pathogenic ★★ same type
- HPS4 p.Glu444Ter Pathogenic/Likely pathogenic ★★ same type
- HPS4 c.1846+3A>G 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/hps4-p-pro247 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown