Is HPSE2 p.Arg592Gln (c.1775G>A) pathogenic?

HPSE2 p.Arg592Gln (c.1775G>A) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely benign (0.142); Ultra-rare (popmax 0.0165%, mid); Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Arg592Gln (c.1775G>A)?

HPSE2 p.Arg592Gln (c.1775G>A) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Arg592Gln (c.1775G>A) in the general population?

HPSE2 p.Arg592Gln (c.1775G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HPSE2 p.Arg592Gln (c.1775G>A)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg592Gln

c.1775G>A · VCV3589310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	27.7	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

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000929% 15/1,614,040 alleles · ultra-rare exomes 11/1,461,842 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,252
South Asian	0.0022%	45,535
Admixed American	0.00167%	60,018
Finnishnot grpmax-eligible	0.00156%	64,026
African / African-American	0.00133%	75,004
European (non-Finnish)	0.000593%	168,568

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.Arg592Gln
Coding: c.1775G>A
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98459578 (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 p.Arg592Ter Uncertain significance ★ same residue
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

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-arg592gln (accessed [today's date]).

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