Is HPS3 p.Ser265fs (c.793del) pathogenic?

HPS3 p.Ser265fs (c.793del) is classified Pathogenic in HPS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-06). Very rare (popmax 0.000254%, nfe).

How common is HPS3 p.Ser265fs (c.793del) in the general population?

HPS3 p.Ser265fs (c.793del) is very rare (popmax 0.000254%, nfe) (gnomAD).

HPS3 p.Ser265fs

c.793del · rs2108129931 · VCV1451694

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

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 3 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP -0.039, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,800 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,598 alleles · very rare

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.Ser265fs
Coding: c.793del
MANE Select: NM_032383
dbSNP: rs2108129931
Type: Deletion
Location: chr3:149141092 (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

Similar variants

HPS3 p.Ala135fs Pathogenic/Likely pathogenic ★★ same type
HPS3 p.Arg284fs Pathogenic ★★ same type
HPS3 p.Arg30fs Pathogenic/Likely pathogenic ★★ same type
HPS3 p.Asn623fs Pathogenic/Likely pathogenic ★★ same type
HPS3 p.Asn83fs Pathogenic/Likely pathogenic ★★ same type
HPS3 p.Asn96fs Likely pathogenic ★★ same type
HPS3 p.Cys417fs Likely pathogenic ★★ same type
HPS3 p.Cys561fs Pathogenic/Likely pathogenic ★★ same type

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-ser265fs (accessed [today's date]).

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