# NM_001098540.3(HPSE):c.684T>G (p.Ser228Arg)

https://sugi.bio/variant/hpse-p-ser228arg

## Summary

**HPSE p.Ser228Arg (c.684T>G)** is classified **Uncertain significance** in HPSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.8456); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HPSE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HPSE](https://sugi.bio/atlas/gene/HPSE/) |
| Protein change (HGVS p.) | p.Ser228Arg |
| Coding change (HGVS c.) | c.684T>G |
| MANE Select transcript | [NM_001098540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098540) |
| Variant type | single nucleotide variant |
| Location | chr4:83310880-83310880 (GRCh38) |
| ClinVar | [VCV4676863](https://www.ncbi.nlm.nih.gov/clinvar/variation/4676863/) |

**All HGVS expressions:** `NC_000004.11:g.84232033A>C`, `NC_000004.12:g.83310880A>C`, `NG_028037.1:g.29274T>G`, `NM_001098540.3:c.684T>G`, `NM_001166498.3:c.684T>G`, `NM_001199830.1:c.510T>G`, `NM_006665.6:c.684T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8456)
- REVEL 0.389 (indeterminate)
- SaProt LLR -10.247 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.298, GERP -2.07, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.01** across the covering region of the MANE Select transcript (83,295,347–83,334,782), spanning 39,435 bp. Chi-square p 0.8. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**HPSE** population constraint: LOEUF 1.066, pLI 4.3299e-09, missense-Z -0.20872. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **228** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.02, 93% of residues very-high.

**58 experimental structure(s)** (PDB): [5E8M](https://www.rcsb.org/structure/5E8M), [5E97](https://www.rcsb.org/structure/5E97), [5E98](https://www.rcsb.org/structure/5E98), [5E9B](https://www.rcsb.org/structure/5E9B), [5E9C](https://www.rcsb.org/structure/5E9C), [5L9Y](https://www.rcsb.org/structure/5L9Y) — incl. mutant structure 5L9Z.

## What this gene does {#gene-function}

*Describes the biological roles of HPSE (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** HPSE's established molecular role includes heparanase activity.


### Pathways affected {#pathways}

HPSE participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** heparanase activity, syndecan binding.

**Biological process:** cell-matrix adhesion, positive regulation of vascular endothelial growth factor production, positive regulation of blood coagulation, heparan sulfate proteoglycan catabolic process, positive regulation of osteoblast proliferation, regulation of hair follicle development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related HPSE variant pages (same residue, condition, or type): [HPSE c.673+8C>A](/variant/hpse-c-673-plus-8c-a), [HPSE p.Gly370Asp](/variant/hpse-p-gly370asp), [HPSE p.Ala177Gly](/variant/hpse-p-ala177gly), [HPSE p.Ala204Thr](/variant/hpse-p-ala204thr), [HPSE p.Ala285Thr](/variant/hpse-p-ala285thr), [HPSE p.Ala305Thr](/variant/hpse-p-ala305thr), [HPSE p.Ala84Thr](/variant/hpse-p-ala84thr), [HPSE p.Arg303Trp](/variant/hpse-p-arg303trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4676863). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*