Is HPSE2 p.Arg294Trp (c.880C>T) pathogenic?

HPSE2 p.Arg294Trp (c.880C>T) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: ambiguous (0.4752); Very rare (popmax 0.00223%, eas); Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Arg294Trp (c.880C>T)?

HPSE2 p.Arg294Trp (c.880C>T) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Arg294Trp (c.880C>T) in the general population?

HPSE2 p.Arg294Trp (c.880C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HPSE2 p.Arg294Trp (c.880C>T)?

AlphaMissense predicts ambiguous (score 0.4752) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg294Trp

c.880C>T · VCV3589606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.4752	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -9.10	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,866 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00167% 27/1,613,452 alleles · very rare exomes 21/1,461,586 · genomes 6/151,866 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,866
European (non-Finnish)	0.00203%	49,161
Admixed American	0.00167%	59,874
Finnishnot grpmax-eligible	0.00156%	63,936

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.Arg294Trp
Coding: c.880C>T
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98721733 (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

urofacial syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.Arg267Trp Uncertain significance ★★ same condition
HPSE2 p.Arg272Gln Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg494His Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg494Leu 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-arg294trp (accessed [today's date]).

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