Is HPS4 p.Pro560= (c.1680G>A) pathogenic?

HPS4 p.Pro560= (c.1680G>A) is classified Conflicting classifications of pathogenicity in HPS4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0198%, nfe); Associated with Hermansky-Pudlak syndrome 4.

What condition is associated with HPS4 p.Pro560= (c.1680G>A)?

HPS4 p.Pro560= (c.1680G>A) is associated with Hermansky-Pudlak syndrome 4 (ClinVar).

How common is HPS4 p.Pro560= (c.1680G>A) in the general population?

HPS4 p.Pro560= (c.1680G>A) is ultra-rare (popmax 0.0198%, nfe) (gnomAD).

HPS4 p.Pro560=

c.1680G>A · rs527653764 · VCV341004

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 0.0198%, nfe)

Conditions

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 -3.1
Overall
CADD	0.309	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0198% European (non-Finnish) · 234/1,180,034 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.016% 258/1,613,920 alleles · ultra-rare exomes 232/1,461,538 · genomes 26/152,382 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)grpmax	0.0198%	5,043
East Asian	0.00446%	22,442
African / African-American	0.004%	25,022
Admixed American	0.00167%	60,026

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro560=
Coding: c.1680G>A
MANE Select: NM_022081
dbSNP: rs527653764
Type: single nucleotide variant
Location: chr22:26463950 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 1 PDB

Full HPS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPS4 p.Pro560Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro560 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown