Is HPS3 p.Arg397Trp (c.1189C>T) pathogenic?

HPS3 p.Arg397Trp (c.1189C>T) is classified Pathogenic/Likely pathogenic in HPS3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-09-11). AlphaMissense: likely pathogenic (0.6166); Ultra-rare (popmax 0.0178%, eas); Associated with HPS3-related disorders.

What condition is associated with HPS3 p.Arg397Trp (c.1189C>T)?

HPS3 p.Arg397Trp (c.1189C>T) is associated with HPS3-related disorders, Hermansky-Pudlak syndrome 3, Hermansky-Pudlak syndrome (ClinVar).

How common is HPS3 p.Arg397Trp (c.1189C>T) in the general population?

HPS3 p.Arg397Trp (c.1189C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about HPS3 p.Arg397Trp (c.1189C>T)?

AlphaMissense predicts likely pathogenic (score 0.6166) — an in-silico prediction, not a clinical call.

HPS3 p.Arg397Trp

c.1189C>T · rs121908316 · VCV4613

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6166 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HPS3-related disorders

Computational evidence

Protein change
AlphaMissense	0.6166	likely pathogenic ✓ concordant with ClinVar
REVEL	0.715	pathogenic-leaning
SaProt	LLR -8.22	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 3.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.0178% East Asian · 8/44,890 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00378% 61/1,613,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,611
African / African-American	0.00534%	18,726
European (non-Finnish)	0.0039%	25,650
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Arg397Trp
Coding: c.1189C>T
MANE Select: NM_032383
dbSNP: rs121908316
Type: single nucleotide variant
Location: chr3:149150624 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.67
Residue 397: a UniProt-annotated variant site (in a colorectal cancer sample; somatic mutation); a UniProt-annotated variant site (in hps3; mild)

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

Disease context

HPS3-related disorders

Also linked: Hermansky-Pudlak syndrome 3 Hermansky-Pudlak syndrome

Similar variants

HPS3 p.Arg397= Likely benign ★ same residue
HPS3 c.1163+1G>A Pathogenic ★★ same condition
HPS3 c.1246-2A>T Likely pathogenic ★★ same condition
HPS3 c.1509+1G>A Likely pathogenic ★★ same condition
HPS3 c.1691+1G>A Pathogenic ★★ same condition
HPS3 c.1692-2A>G Likely pathogenic ★★ same condition
HPS3 c.1873-1G>A Likely pathogenic ★★ same condition
HPS3 c.2106+1G>T 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-arg397trp (accessed [today's date]).

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