HPS4 p.Pro206=
c.618G>A · rs139165558 · VCV740692
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0701%, amr)
Conditions
1
Hermansky-Pudlak syndrome 4
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 -11 | GERP -3.6 |
| Overall | ||
| CADD | 1.62 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0701%
Admixed American · 42/59,954 alleles
Filtering AF
0.0533%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0474%
Overall
0.0143%
230/1,608,962 alleles · ultra-rare
exomes 169/1,456,934 · genomes 61/152,028 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0701% | 1,427 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0609% | 1,641 |
| African / African-American | 0.0454% | 2,202 |
| Remaining individualsnot grpmax-eligible | 0.0273% | 3,666 |
| Middle Eastern | 0.0165% | 6,052 |
| European (non-Finnish) | 0.00995% | 10,054 |
| Finnishnot grpmax-eligible | 0.00158% | 63,214 |
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.Pro206=
- Coding
- c.618G>A
- MANE Select
- NM_022081
- dbSNP
- rs139165558
- Type
- single nucleotide variant
- Location
- chr22:26468602 (GRCh38)
- Gene constraint
- LOEUF 0.794 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 62.83 · 1 PDB
Similar variants
- HPS4 p.Pro206Leu Uncertain significance ★★ ⚠ same residue
- HPS4 c.133-2A>G Likely pathogenic ★★ same condition
- HPS4 c.706+1G>A Pathogenic/Likely pathogenic ★★ same condition
- HPS4 p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
- HPS4 p.Gln378Ter Pathogenic/Likely pathogenic ★★ same condition
- HPS4 p.Gln50Ter Likely pathogenic ★★ same condition
- HPS4 p.Gln516Ter Pathogenic/Likely pathogenic ★★ same condition
- HPS4 p.Glu444Ter Pathogenic/Likely pathogenic ★★ 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/hps4-p-pro206 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown