Is HPSE p.Phe398Leu (c.1194C>G) pathogenic?

HPSE p.Phe398Leu (c.1194C>G) is classified Uncertain significance in HPSE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.5787); Absent from gnomAD v4.1.

How common is HPSE p.Phe398Leu (c.1194C>G) in the general population?

HPSE p.Phe398Leu (c.1194C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPSE p.Phe398Leu (c.1194C>G)?

AlphaMissense predicts likely pathogenic (score 0.5787) — an in-silico prediction, not a clinical call.

HPSE p.Phe398Leu

c.1194C>G · VCV3526529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5787 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5787	likely pathogenic
REVEL	0.134	moderately benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.9	GERP -3.2
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	3.187	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.Phe398Leu
Coding: c.1194C>G
MANE Select: NM_001098540
Type: single nucleotide variant
Location: chr4:83306215 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB
Residue 398: the 'required for heterodimerization with the heparanase 8 kda subunit' region

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

Similar variants

HPSE p.Phe398Val Uncertain significance ★ ⚠ same residue
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

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-phe398leu (accessed [today's date]).

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