Is HPS3 p.Pro738= (c.2214T>G) pathogenic?

HPS3 p.Pro738= (c.2214T>G) is classified Uncertain significance in HPS3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-06). Very rare (popmax 0.00223%, eas); Associated with Hermansky-Pudlak syndrome.

What condition is associated with HPS3 p.Pro738= (c.2214T>G)?

HPS3 p.Pro738= (c.2214T>G) is associated with Hermansky-Pudlak syndrome (ClinVar).

How common is HPS3 p.Pro738= (c.2214T>G) in the general population?

HPS3 p.Pro738= (c.2214T>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Hermansky-Pudlak syndrome inherited?

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

HPS3 p.Pro738=

c.2214T>G · VCV4069493

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Hermansky-Pudlak syndrome

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 -0.98	GERP -1.8, phastCons 0.005
Overall
CADD	4.954	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Overall 6.2e-05% 1/1,614,022 alleles · very rare exomes 1/1,461,686 · genomes 0/152,336 · joint denominator

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: HPS3
Protein: p.Pro738=
Coding: c.2214T>G
MANE Select: NM_032383
Type: single nucleotide variant
Location: chr3:149162255 (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 p.Pro738Ser Uncertain significance ★ ⚠ same residue
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

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-pro738 (accessed [today's date]).

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