Is HPSE p.Asp476Glu (c.1428T>G) pathogenic?

HPSE p.Asp476Glu (c.1428T>G) is classified Likely benign in HPSE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-20). AlphaMissense: ambiguous (0.4015); Rare (popmax 0.171%, nfe); Associated with HPSE-related disorder.

What condition is associated with HPSE p.Asp476Glu (c.1428T>G)?

HPSE p.Asp476Glu (c.1428T>G) is associated with HPSE-related disorder (ClinVar).

How common is HPSE p.Asp476Glu (c.1428T>G) in the general population?

HPSE p.Asp476Glu (c.1428T>G) is rare (popmax 0.171%, nfe) (gnomAD).

What do computational predictors say about HPSE p.Asp476Glu (c.1428T>G)?

AlphaMissense predicts ambiguous (score 0.4015) — an in-silico prediction, not a clinical call.

HPSE p.Asp476Glu

c.1428T>G · rs145560091 · VCV3045667

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4015 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.171%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

HPSE-related disorder

Computational evidence

Protein change
AlphaMissense	0.4015	ambiguous
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.59	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -3.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	8.265	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 0.171% European (non-Finnish) · 2,015/1,177,008 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.132% 2,131/1,609,760 alleles · rare exomes 2,019/1,457,560 · genomes 112/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.171%	584
Remaining individualsnot grpmax-eligible	0.0898%	1,113
Admixed American	0.0385%	2,596
Finnishnot grpmax-eligible	0.0312%	3,201
African / African-American	0.0174%	5,747
South Asian	0.00441%	22,677

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: HPSE
Protein: p.Asp476Glu
Coding: c.1428T>G
MANE Select: NM_001098540
dbSNP: rs145560091
Type: single nucleotide variant
Location: chr4:83301004 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB
Residue 476: a β-strand

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

Disease context

HPSE-related disorder

Similar variants

HPSE p.Ala352= Likely benign same condition
HPSE p.Asn459= Benign same condition
HPSE p.His436= Likely benign same condition
HPSE p.Lys161Gln Benign same condition
HPSE p.Lys307Arg Benign same condition
HPSE p.Phe236Cys Likely benign same condition
HPSE c.673+8C>A Benign ★★ same type
HPSE p.Gly370Asp Likely benign ★★ 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-asp476glu (accessed [today's date]).

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