Is HPSE p.Pro133Thr (c.397C>A) pathogenic?

HPSE p.Pro133Thr (c.397C>A) is classified Uncertain significance in HPSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0929); Absent from gnomAD v4.1.

How common is HPSE p.Pro133Thr (c.397C>A) in the general population?

HPSE p.Pro133Thr (c.397C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPSE p.Pro133Thr (c.397C>A)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

HPSE p.Pro133Thr

c.397C>A · VCV4272096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	21.6	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: HPSE
Protein: p.Pro133Thr
Coding: c.397C>A
MANE Select: NM_001098540
Type: single nucleotide variant
Location: chr4:83319446 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB

Full HPSE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HPSE c.673+8C>A Benign ★★ same type
HPSE p.Gly370Asp Likely benign ★★ same type
HPSE p.Ala177Gly Uncertain significance ★ ⚠ same type
HPSE p.Ala204Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala285Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala305Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala84Thr Uncertain significance ★ ⚠ same type
HPSE p.Arg303Trp Uncertain significance ★ ⚠ 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/hpse-p-pro133thr (accessed [today's date]).

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