Is HPSE2 p.Arg506Ter (c.1516C>T) pathogenic?

HPSE2 p.Arg506Ter (c.1516C>T) is classified Pathogenic/Likely pathogenic in HPSE2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-01-25). Ultra-rare (popmax 0.0111%, eas); Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Arg506Ter (c.1516C>T)?

HPSE2 p.Arg506Ter (c.1516C>T) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Arg506Ter (c.1516C>T) in the general population?

HPSE2 p.Arg506Ter (c.1516C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

HPSE2 p.Arg506Ter

c.1516C>T · rs267606866 · VCV83

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 12
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP -0.49, phastCons 1
Overall
CADD	44.0	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 0.0111% East Asian · 5/44,884 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00124% 20/1,613,974 alleles · ultra-rare exomes 18/1,461,830 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,080
European (non-Finnish)	0.000847%	117,999

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.Arg506Ter
Coding: c.1516C>T
MANE Select: NM_021828
dbSNP: rs267606866
Type: single nucleotide variant
Location: chr10:98482733 (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.Arg506Gln 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.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-arg506ter (accessed [today's date]).

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