Is HPSE2 p.Lys252Arg (c.755A>G) pathogenic?

HPSE2 p.Lys252Arg (c.755A>G) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-07). AlphaMissense: likely benign (0.1162); Absent from gnomAD v4.1; Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Lys252Arg (c.755A>G)?

HPSE2 p.Lys252Arg (c.755A>G) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Lys252Arg (c.755A>G) in the general population?

HPSE2 p.Lys252Arg (c.755A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPSE2 p.Lys252Arg (c.755A>G)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

HPSE2 p.Lys252Arg

c.755A>G · VCV3589642

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.85	donor gain · deltas
Pangolin	Δ0.72	gain · loss 0.37 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HPSE2
Protein: p.Lys252Arg
Coding: c.755A>G
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98743912 (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-lys252arg (accessed [today's date]).

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