Is HPSE2 p.Arg592Ter (c.1774C>T) pathogenic?

HPSE2 p.Arg592Ter (c.1774C>T) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). Ultra-rare (popmax 0.0367%, amr); Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Arg592Ter (c.1774C>T)?

HPSE2 p.Arg592Ter (c.1774C>T) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Arg592Ter (c.1774C>T) in the general population?

HPSE2 p.Arg592Ter (c.1774C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

HPSE2 p.Arg592Ter

c.1774C>T · VCV3589317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.4, phastCons 1
Overall
CADD	46.0	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 0.0367% Admixed American · 22/60,018 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00304% 49/1,614,078 alleles · ultra-rare exomes 30/1,461,854 · genomes 19/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,250
African / African-American	0.00267%	37,509
East Asian	0.00223%	44,864
European (non-Finnish)	0.00169%	58,999
South Asian	0.0011%	91,080

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.Arg592Ter
Coding: c.1774C>T
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98459579 (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.Arg592Gln 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-arg592ter (accessed [today's date]).

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