Is HPSE2 c.784+189del pathogenic?

HPSE2 c.784+189del is classified Benign in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-12). Common (popmax 50.4%, sas) — too common for a highly-penetrant pathogenic allele.

HPSE2 c.784+189del

Q: How common is HPSE2 c.784+189del in the general population?

HPSE2 c.784+189del is common (popmax 50.4%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs34603601 · VCV1282817

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 50.4%, sas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +189	deep intronic (+189 nt into the intron)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.59	GERP -3.5
Non-coding constraint	Z 1.75	1 kb window · o/e 0.85 · regional · uncalibrated
Overall
CADD	6.693	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50.4% South Asian · 2,429/4,820 alleles

Filtering AF 48.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 48%

Overall 36.9% 56,129/152,030 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	51%	2
Amishnot grpmax-eligible	50.9%	2
South Asiangrpmax	50.4%	2
European (non-Finnish)	47.5%	2
Middle Eastern	43.9%	2
Finnishnot grpmax-eligible	43.7%	2
Remaining individualsnot grpmax-eligible	40.3%	2
East Asian	39.7%	3
Admixed American	38.2%	3
African / African-American	13.9%	7

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HPSE2
Coding: c.784+189del
MANE Select: NM_021828
dbSNP: rs34603601
Type: Deletion
Location: chr10:98743694 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.90

Full HPSE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HPSE2 p.Asn489fs Pathogenic/Likely pathogenic ★★ same type
HPSE2 p.Asp84fs Likely pathogenic ★ same type
HPSE2 p.Phe436fs Likely pathogenic ★ same type
HPSE2 p.Pro470fs Likely pathogenic ★ same type
HPSE2 p.Thr370_Tyr371insTer Likely pathogenic ★ same type
HPSE2 p.Val382fs Likely pathogenic ★ same type
HPSE2 c.1614-188del Benign ★ same type
HPSE2 c.785-99del Benign ★ 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/hpse2-c-784-plus-189del (accessed [today's date]).

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