Is HPSE2 p.Pro140Arg (c.419C>G) pathogenic?

HPSE2 p.Pro140Arg (c.419C>G) is classified Uncertain significance in HPSE2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-06-06). AlphaMissense: likely pathogenic (0.7035); Very rare (popmax 0.00131%, nfe); Associated with Ochoa syndrome.

What condition is associated with HPSE2 p.Pro140Arg (c.419C>G)?

HPSE2 p.Pro140Arg (c.419C>G) is associated with Ochoa syndrome (ClinVar).

How common is HPSE2 p.Pro140Arg (c.419C>G) in the general population?

HPSE2 p.Pro140Arg (c.419C>G) is very rare (popmax 0.00131%, nfe) (gnomAD).

What do computational predictors say about HPSE2 p.Pro140Arg (c.419C>G)?

AlphaMissense predicts likely pathogenic (score 0.7035) — an in-silico prediction, not a clinical call.

HPSE2 p.Pro140Arg

c.419C>G · rs967685128 · VCV1691126

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00131%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ochoa syndrome

Computational evidence

Protein change
AlphaMissense	0.7035	likely pathogenic
REVEL	0.255	benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	23.7	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

Grpmax group 0.00131% European (non-Finnish) · 15/1,146,996 alleles

Filtering AF 0.000785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000623%

Overall 0.000967% 15/1,551,526 alleles · very rare exomes 15/1,399,262 · genomes 0/152,264 · joint denominator

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.Pro140Arg
Coding: c.419C>G
MANE Select: NM_021828
dbSNP: rs967685128
Type: single nucleotide variant
Location: chr10:99232377 (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

Ochoa syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPSE2 p.Pro140Ala Uncertain significance ★ ⚠ same residue
HPSE2 c.1099-1G>A Pathogenic ★★ same condition
HPSE2 p.Tyr143Ter Pathogenic ★ same condition
HPSE2 p.Pro140_Asp141insGlyPro Uncertain significance ★ same residue
HPSE2 c.(1099-?_1320+1 Uncertain significance same condition
HPSE2 c.(610+1_611-1 Uncertain significance same condition
HPSE2 c.291-1G>T Likely pathogenic ★★ same type
HPSE2 p.Arg153Ter Pathogenic/Likely pathogenic ★★ same type

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-pro140arg (accessed [today's date]).

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