Is HPSE2 p.Gln40Pro (c.119A>C) pathogenic?

HPSE2 p.Gln40Pro (c.119A>C) is classified Uncertain significance in HPSE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-05). AlphaMissense: likely benign (0.0656); Rare (popmax 0.477%, eas); Associated with urofacial syndrome type 1.

What condition is associated with HPSE2 p.Gln40Pro (c.119A>C)?

HPSE2 p.Gln40Pro (c.119A>C) is associated with urofacial syndrome type 1 (ClinVar).

How common is HPSE2 p.Gln40Pro (c.119A>C) in the general population?

HPSE2 p.Gln40Pro (c.119A>C) is rare (popmax 0.477%, eas) (gnomAD).

What do computational predictors say about HPSE2 p.Gln40Pro (c.119A>C)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

HPSE2 p.Gln40Pro

c.119A>C · VCV3526538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.477%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

urofacial syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.29	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -3.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	19.97	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 0.477% East Asian · 214/44,840 alleles

Filtering AF 0.425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.405%

Overall 0.0137% 221/1,613,904 alleles · rare exomes 209/1,461,886 · genomes 12/152,018 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.477%	210
Remaining individualsnot grpmax-eligible	0.0112%	8,930

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.Gln40Pro
Coding: c.119A>C
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:99235684 (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.Gln40Arg 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-gln40pro (accessed [today's date]).

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