Is HPSE p.Lys307Arg (c.920A>G) pathogenic?

HPSE p.Lys307Arg (c.920A>G) is classified Benign in HPSE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). AlphaMissense: likely benign (0.0693); Common (popmax 85.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with HPSE-related disorder.

What condition is associated with HPSE p.Lys307Arg (c.920A>G)?

HPSE p.Lys307Arg (c.920A>G) is associated with HPSE-related disorder (ClinVar).

What do computational predictors say about HPSE p.Lys307Arg (c.920A>G)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

HPSE p.Lys307Arg

Q: How common is HPSE p.Lys307Arg (c.920A>G) in the general population?

HPSE p.Lys307Arg (c.920A>G) is common (popmax 85.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.920A>G · rs11099592 · VCV3060058

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 85.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HPSE-related disorder

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	17.34	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 85.2% African / African-American · 62,828/73,754 alleles

Filtering AF 84.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.4%

Overall 78% 1,228,002/1,573,576 alleles · common exomes 1,106,906/1,421,368 · genomes 121,096/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	85.2%	1
East Asian	84.9%	1
Ashkenazi Jewishnot grpmax-eligible	79.5%	1
South Asian	78.8%	1
Remaining individualsnot grpmax-eligible	78.6%	1
Middle Eastern	77.7%	1
European (non-Finnish)	77.6%	1
Finnishnot grpmax-eligible	76.3%	1
Admixed American	71.2%	1
Amishnot grpmax-eligible	61.3%	2

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.Lys307Arg
Coding: c.920A>G
MANE Select: NM_001098540
dbSNP: rs11099592
Type: single nucleotide variant
Location: chr4:83309466 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB
Residue 307: a UniProt-annotated variant site (in); the 'required for heterodimerization with the heparanase 8 kda subunit' region; an α-helix

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.Asp476Glu Likely benign same condition
HPSE p.His436= Likely benign same condition
HPSE p.Lys161Gln 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-lys307arg (accessed [today's date]).

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