Is HPS3 p.Phe251Ser (c.752T>C) pathogenic?

HPS3 p.Phe251Ser (c.752T>C) is classified Uncertain significance in HPS3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely pathogenic (0.7611); Absent from gnomAD v4.1; Associated with Hermansky-Pudlak syndrome.

What condition is associated with HPS3 p.Phe251Ser (c.752T>C)?

HPS3 p.Phe251Ser (c.752T>C) is associated with Hermansky-Pudlak syndrome (ClinVar).

How common is HPS3 p.Phe251Ser (c.752T>C) in the general population?

HPS3 p.Phe251Ser (c.752T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hermansky-Pudlak syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HPS3 p.Phe251Ser (c.752T>C)?

AlphaMissense predicts likely pathogenic (score 0.7611) — an in-silico prediction, not a clinical call.

HPS3 p.Phe251Ser

c.752T>C · VCV4069496

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7611 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hermansky-Pudlak syndrome

Computational evidence

Protein change
AlphaMissense	0.7611	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HPS3
Protein: p.Phe251Ser
Coding: c.752T>C
MANE Select: NM_032383
Type: single nucleotide variant
Location: chr3:149141056 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.67

Full HPS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hermansky-Pudlak syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

HPS3 c.1163+1G>A Pathogenic ★★ same condition
HPS3 c.1691+1G>A Pathogenic ★★ same condition
HPS3 p.Arg397Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
HPS3 p.Arg530Ter Pathogenic/Likely pathogenic ★★ same condition
HPS3 p.Gln245Ter Pathogenic/Likely pathogenic ★★ same condition
HPS3 p.Gln368Ter Likely pathogenic ★★ same condition
HPS3 p.Glu275Ter Likely pathogenic ★★ same condition
HPS3 p.Glu621Ter 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/hps3-p-phe251ser (accessed [today's date]).

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