Is HPS1 p.Phe149= (c.447C>T) pathogenic?

HPS1 p.Phe149= (c.447C>T) is classified Likely benign in HPS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0222%, nfe); Associated with Hermansky-Pudlak syndrome.

What condition is associated with HPS1 p.Phe149= (c.447C>T)?

HPS1 p.Phe149= (c.447C>T) is associated with Hermansky-Pudlak syndrome (ClinVar).

How common is HPS1 p.Phe149= (c.447C>T) in the general population?

HPS1 p.Phe149= (c.447C>T) is ultra-rare (popmax 0.0222%, nfe) (gnomAD).

How is Hermansky-Pudlak syndrome inherited?

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

HPS1 p.Phe149=

c.447C>T · rs564896584 · VCV752245

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, nfe)

Conditions

Hermansky-Pudlak syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.103	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.3, phastCons 1
Overall
CADD	12.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0222% European (non-Finnish) · 255/1,149,314 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0168% 262/1,555,260 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0222%	4,507
Remaining individualsnot grpmax-eligible	0.00664%	15,069
Finnishnot grpmax-eligible	0.00337%	29,674
African / African-American	0.00136%	73,514

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.Phe149=
Coding: c.447C>T
MANE Select: NM_000195
dbSNP: rs564896584
Type: single nucleotide variant
Location: chr10:98434043 (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 — 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

HPS1 c.1744-2A>C Pathogenic/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+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
HPS1 c.398+5G>A Pathogenic/Likely pathogenic ★★ same condition
HPS1 c.399-2A>G 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-phe149 (accessed [today's date]).

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