Is HPSE2 p.Ala20fs (c.57dup) pathogenic?

HPSE2 p.Ala20fs (c.57dup) is classified Pathogenic in HPSE2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-14). Ultra-rare (popmax 0.0112%, eas); Associated with HPSE2-related disorder.

What condition is associated with HPSE2 p.Ala20fs (c.57dup)?

HPSE2 p.Ala20fs (c.57dup) is associated with HPSE2-related disorder, urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Ala20fs (c.57dup) in the general population?

HPSE2 p.Ala20fs (c.57dup) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

HPSE2 p.Ala20fs

c.57dup · rs778121647 · VCV90

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

HPSE2-related disorder

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 1 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.95	GERP -2.9, phastCons 0.96
Overall
CADD	23.4	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 0.0112% East Asian · 5/44,808 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00279% 45/1,613,290 alleles · ultra-rare exomes 39/1,461,412 · genomes 6/151,878 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0157%	6,373
East Asiangrpmax	0.0112%	8,962
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
South Asian	0.00439%	22,759
African / African-American	0.004%	24,974
Admixed American	0.00333%	29,985
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00144%	69,398

Finnish 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
Protein: p.Ala20fs
Coding: c.57dup
MANE Select: NM_021828
dbSNP: rs778121647
Type: Duplication
Location: chr10:99235745 (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

Disease context

HPSE2-related disorder

Also linked: urofacial syndrome type 1

Similar variants

HPSE2 c.957-28_957-19dup Benign/Likely benign ★★ same condition
HPSE2 c.1099-1G>A Pathogenic ★★ same condition
HPSE2 c.291-1G>T Likely pathogenic ★★ same condition
HPSE2 p.Arg153Ter Pathogenic/Likely pathogenic ★★ same condition
HPSE2 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same condition
HPSE2 p.Asn489fs Pathogenic/Likely pathogenic ★★ same condition
HPSE2 p.Arg267Trp Uncertain significance ★★ same condition
HPSE2 p.Arg272Gln Uncertain significance ★★ ⚠ 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/hpse2-p-ala20fs (accessed [today's date]).

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