Is HPS3 p.Pro370fs (c.1107del) pathogenic?

HPS3 p.Pro370fs (c.1107del) is classified Pathogenic/Likely pathogenic in HPS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-16). Very rare (popmax 0.00169%, nfe); Associated with HPS3-related disorders.

What condition is associated with HPS3 p.Pro370fs (c.1107del)?

HPS3 p.Pro370fs (c.1107del) is associated with HPS3-related disorders (ClinVar).

How common is HPS3 p.Pro370fs (c.1107del) in the general population?

HPS3 p.Pro370fs (c.1107del) is very rare (popmax 0.00169%, nfe) (gnomAD).

HPS3 p.Pro370fs

c.1107del · rs1421926305 · VCV2141063

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

HPS3-related disorders

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 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,020 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,614,052 alleles · very rare exomes 18/1,461,844 · genomes 2/152,208 · joint denominator

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.Pro370fs
Coding: c.1107del
MANE Select: NM_032383
dbSNP: rs1421926305
Type: Deletion
Location: chr3:149145490 (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

HPS3-related disorders

Similar variants

HPS3 p.Pro370_Ser373del Likely pathogenic ★★ same residue
HPS3 c.1163+1G>A Pathogenic ★★ same condition
HPS3 c.1692-2A>G Likely pathogenic ★★ same condition
HPS3 p.Arg397Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
HPS3 p.Ala135Gly Uncertain significance ★★ ⚠ same condition
HPS3 c.2292+7C>T Conflicting classifications of pathogenicity ★ same condition
HPS3 p.Met1Leu Conflicting classifications of pathogenicity ★ same condition
HPS3 p.Gln749Ter 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-pro370fs (accessed [today's date]).

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