Is HPS3 p.Ala416fs (c.1246_1247insT) pathogenic?

HPS3 p.Ala416fs (c.12461247insT) is classified Pathogenic/Likely pathogenic in HPS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-14). Absent from gnomAD; Associated with Hermansky-Pudlak syndrome 3.

What condition is associated with HPS3 p.Ala416fs (c.1246_1247insT)?

HPS3 p.Ala416fs (c.1246_1247insT) is associated with Hermansky-Pudlak syndrome 3 (ClinVar).

How common is HPS3 p.Ala416fs (c.1246_1247insT) in the general population?

HPS3 p.Ala416fs (c.1246_1247insT) is absent from gnomAD (gnomAD).

HPS3 p.Ala416fs

c.1246_1247insT · rs2473099287 · VCV2676088

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Hermansky-Pudlak syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HPS3
Protein: p.Ala416fs
Coding: c.1246_1247insT
MANE Select: NM_032383
dbSNP: rs2473099287
Type: Insertion
Location: chr3:149153494 (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.Ser244fs Pathogenic ★★ same condition
HPS3 p.Leu207fs Likely pathogenic ★ same condition
HPS3 p.Lys264fs Likely pathogenic ★ same condition
HPS3 p.Met201fs Likely pathogenic ★ same condition
HPS3 p.Ala416Pro 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

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-ala416fs (accessed [today's date]).

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