Is HPSE p.Arg303Trp (c.907C>T) pathogenic?

HPSE p.Arg303Trp (c.907C>T) is classified Uncertain significance in HPSE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely benign (0.2066); Ultra-rare (popmax 0.07%, sas).

How common is HPSE p.Arg303Trp (c.907C>T) in the general population?

HPSE p.Arg303Trp (c.907C>T) is ultra-rare (popmax 0.07%, sas) (gnomAD).

What do computational predictors say about HPSE p.Arg303Trp (c.907C>T)?

AlphaMissense predicts likely benign (score 0.2066) — an in-silico prediction, not a clinical call.

HPSE p.Arg303Trp

c.907C>T · VCV3284748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.07%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2066	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.07% South Asian · 60/85,716 alleles

Filtering AF 0.0558% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0506%

Overall 0.0068% 105/1,543,224 alleles · ultra-rare exomes 96/1,391,042 · genomes 9/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.07%	1,429
Admixed American	0.0371%	2,694
East Asian	0.00909%	11,005
Remaining individualsnot grpmax-eligible	0.00667%	14,996
African / African-American	0.00413%	24,242
Finnishnot grpmax-eligible	0.00313%	31,932
European (non-Finnish)	0.000978%	102,230

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.Arg303Trp
Coding: c.907C>T
MANE Select: NM_001098540
Type: single nucleotide variant
Location: chr4:83309479 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB
Residue 303: a binding site; the 'required for heterodimerization with the heparanase 8 kda subunit' region; a turn

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.Arg517Gln 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-arg303trp (accessed [today's date]).

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