Is HPS4 p.Pro338= (c.1014C>T) pathogenic?

HPS4 p.Pro338= (c.1014C>T) is classified Conflicting classifications of pathogenicity in HPS4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0117%, amr); Associated with Hermansky-Pudlak syndrome 4.

What condition is associated with HPS4 p.Pro338= (c.1014C>T)?

HPS4 p.Pro338= (c.1014C>T) is associated with Hermansky-Pudlak syndrome 4 (ClinVar).

How common is HPS4 p.Pro338= (c.1014C>T) in the general population?

HPS4 p.Pro338= (c.1014C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

HPS4 p.Pro338=

c.1014C>T · rs188300485 · VCV903530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

Hermansky-Pudlak syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.3	GERP -2.1
Overall
CADD	0.407	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,030 alleles

Filtering AF 0.00757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00768% 124/1,614,170 alleles · ultra-rare exomes 113/1,461,848 · genomes 11/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,576
European (non-Finnish)	0.00898%	11,132
African / African-American	0.00666%	15,009
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.0022%	45,542

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: HPS4
Protein: p.Pro338=
Coding: c.1014C>T
MANE Select: NM_022081
dbSNP: rs188300485
Type: single nucleotide variant
Location: chr22:26464616 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.83 · 1 PDB

Full HPS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPS4 c.133-2A>G Likely pathogenic ★★ same condition
HPS4 c.706+1G>A Pathogenic/Likely pathogenic ★★ same condition
HPS4 p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
HPS4 p.Gln378Ter Pathogenic/Likely pathogenic ★★ same condition
HPS4 p.Gln50Ter Likely pathogenic ★★ same condition
HPS4 p.Gln516Ter Pathogenic/Likely pathogenic ★★ same condition
HPS4 p.Glu444Ter Pathogenic/Likely pathogenic ★★ same condition
HPS4 c.*1227T>C Uncertain significance ★★ 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/hps4-p-pro338 (accessed [today's date]).

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