Is HPS3 p.Ala403Val (c.1208C>T) pathogenic?

HPS3 p.Ala403Val (c.1208C>T) is classified Uncertain significance in HPS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.1893); Ultra-rare (popmax 0.02%, amr); Associated with Hermansky-Pudlak syndrome 3.

What condition is associated with HPS3 p.Ala403Val (c.1208C>T)?

HPS3 p.Ala403Val (c.1208C>T) is associated with Hermansky-Pudlak syndrome 3 (ClinVar).

How common is HPS3 p.Ala403Val (c.1208C>T) in the general population?

HPS3 p.Ala403Val (c.1208C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about HPS3 p.Ala403Val (c.1208C>T)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

HPS3 p.Ala403Val

c.1208C>T · rs773950483 · VCV343704

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hermansky-Pudlak syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.79 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,008 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000805% 13/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
European (non-Finnish)	8.47e-05%	1,179,970

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.Ala403Val
Coding: c.1208C>T
MANE Select: NM_032383
dbSNP: rs773950483
Type: single nucleotide variant
Location: chr3:149150643 (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 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPS3 p.Ala403Ser Uncertain significance ★★ ⚠ 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.1873-1G>A Likely pathogenic ★★ same condition
HPS3 c.2106+1G>T Likely pathogenic ★★ same condition
HPS3 c.2292+1G>A Likely pathogenic ★★ same condition
HPS3 p.Arg107Ter 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-ala403val (accessed [today's date]).

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