Is HPSE2 p.Pro140Ala (c.418C>G) pathogenic?

HPSE2 p.Pro140Ala (c.418C>G) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: ambiguous (0.3718); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HPSE2 p.Pro140Ala (c.418C>G)?

HPSE2 p.Pro140Ala (c.418C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HPSE2 p.Pro140Ala (c.418C>G) in the general population?

HPSE2 p.Pro140Ala (c.418C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPSE2 p.Pro140Ala (c.418C>G)?

AlphaMissense predicts ambiguous (score 0.3718) — an in-silico prediction, not a clinical call.

HPSE2 p.Pro140Ala

c.418C>G · VCV4036193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3718 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3718	ambiguous
REVEL	0.166	moderately benign-leaning
SaProt	LLR -5.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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.Pro140Ala
Coding: c.418C>G
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:99232378 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPSE2 p.Pro140Arg Uncertain significance ⚠ same residue
HPSE2 p.Arg267Trp Uncertain significance ★★ same condition
HPSE2 p.Arg494His Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg494Leu Uncertain significance ★★ same condition
HPSE2 p.Arg590His Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg590Ser Uncertain significance ★★ ⚠ same condition
HPSE2 p.Asn237Ser Uncertain significance ★★ ⚠ same condition
HPSE2 p.Asp171Gly 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-pro140ala (accessed [today's date]).

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