Is HPS1 p.Pro461= (c.1383C>T) pathogenic?

HPS1 p.Pro461= (c.1383C>T) is classified Likely benign in HPS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). Ultra-rare (popmax 0.021%, sas); Associated with Hermansky-Pudlak syndrome 1.

What condition is associated with HPS1 p.Pro461= (c.1383C>T)?

HPS1 p.Pro461= (c.1383C>T) is associated with Hermansky-Pudlak syndrome 1 (ClinVar).

How common is HPS1 p.Pro461= (c.1383C>T) in the general population?

HPS1 p.Pro461= (c.1383C>T) is ultra-rare (popmax 0.021%, sas) (gnomAD).

HPS1 p.Pro461=

c.1383C>T · rs763241171 · VCV1102527

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, sas)

Conditions

Hermansky-Pudlak syndrome 1

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 -6.2	GERP -3.2
Overall
CADD	5.727	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.021% South Asian · 19/90,608 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0044% 71/1,612,574 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.021%	4,769
European (non-Finnish)	0.00398%	25,095
Admixed American	0.00334%	29,934
Remaining individualsnot grpmax-eligible	0.0032%	31,226
East Asian	0.00223%	44,878

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: HPS1
Protein: p.Pro461=
Coding: c.1383C>T
MANE Select: NM_000195
dbSNP: rs763241171
Type: single nucleotide variant
Location: chr10:98424327 (GRCh38)
Gene constraint: LOEUF 0.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 1 PDB

Full HPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPS1 p.Pro461Ser Uncertain significance ★ ⚠ same residue
HPS1 c.1335+1G>A Likely pathogenic ★★ same condition
HPS1 c.1744-2A>C Pathogenic/Likely pathogenic ★★ same condition
HPS1 c.1857+1G>A Likely pathogenic ★★ same condition
HPS1 c.1857+2T>C Pathogenic/Likely pathogenic ★★ same condition
HPS1 c.1858-1G>A Pathogenic/Likely pathogenic ★★ same condition
HPS1 c.1940+2T>C Pathogenic/Likely pathogenic ★★ same condition
HPS1 c.398+2T>C 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/hps1-p-pro461 (accessed [today's date]).

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