Is HPS5 p.Pro564= (c.1692T>C) pathogenic?

HPS5 p.Pro564= (c.1692T>C) is classified Conflicting classifications of pathogenicity in HPS5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0456%, nfe); Associated with Hermansky-Pudlak syndrome 5.

What condition is associated with HPS5 p.Pro564= (c.1692T>C)?

HPS5 p.Pro564= (c.1692T>C) is associated with Hermansky-Pudlak syndrome 5 (ClinVar).

How common is HPS5 p.Pro564= (c.1692T>C) in the general population?

HPS5 p.Pro564= (c.1692T>C) is ultra-rare (popmax 0.0456%, nfe) (gnomAD).

HPS5 p.Pro564=

c.1692T>C · rs150590027 · VCV879743

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 0.0456%, nfe)

Conditions

Hermansky-Pudlak syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.082	GERP -5.5, phastCons 0.11
Overall
CADD	7.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0456% European (non-Finnish) · 538/1,180,028 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0377% 609/1,614,080 alleles · ultra-rare exomes 570/1,461,872 · genomes 39/152,208 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.104%	961
European (non-Finnish)grpmax	0.0456%	2,193
African / African-American	0.00667%	14,988
Admixed American	0.00167%	60,004

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: HPS5
Protein: p.Pro564=
Coding: c.1692T>C
MANE Select: NM_181507
dbSNP: rs150590027
Type: single nucleotide variant
Location: chr11:18295112 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.21
Residue 564: the 'disordered' region

Full HPS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPS5 p.Pro564Ser Uncertain significance ★★ ⚠ same residue
HPS5 c.1862+1G>A Likely pathogenic ★★ same condition
HPS5 c.2718-2A>G Pathogenic/Likely pathogenic ★★ same condition
HPS5 c.2837+1G>A Likely pathogenic ★★ same condition
HPS5 c.478-2A>G Likely pathogenic ★★ same condition
HPS5 c.825-1G>A Pathogenic/Likely pathogenic ★★ same condition
HPS5 c.986-1G>C Likely pathogenic ★★ same condition
HPS5 p.Gln473Ter 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/hps5-p-pro564 (accessed [today's date]).

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