# NM_021828.5(HPSE2):c.1407del (p.Pro470fs)

https://sugi.bio/variant/hpse2-p-pro470fs

## Summary

**HPSE2 p.Pro470fs (c.1407del)** is classified **Likely pathogenic** in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-15). Very rare (popmax 0.00133%, afr); Associated with urofacial syndrome type 1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the HPSE2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to urofacial syndrome type 1.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024666/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HPSE2](https://sugi.bio/atlas/gene/HPSE2/) |
| Protein change (HGVS p.) | p.Pro470fs |
| Coding change (HGVS c.) | c.1407del |
| MANE Select transcript | [NM_021828](https://www.ncbi.nlm.nih.gov/nuccore/NM_021828) |
| Variant type | Deletion |
| Location | chr10:98490110-98490110 (GRCh38) |
| ClinVar | [VCV3589444](https://www.ncbi.nlm.nih.gov/clinvar/variation/3589444/) |

**All HGVS expressions:** `NC_000010.10:g.100249868del`, `NC_000010.11:g.98490111del`, `NG_023416.1:g.750766del`, `NG_023416.2:g.830841del`, `NM_001166244.1:c.1233del`, `NM_001166245.1:c.1071del`, `NM_001166246.1:c.1407del`, `NM_021828.5:c.1407del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.846, GERP 1.88, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.837, pLI 5.9825e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 26.8**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,928 in the highest group · 1/1,614,096 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**HPSE2** population constraint: LOEUF 0.837, pLI 5.9825e-07, missense-Z 0.61691; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.90, 63% of residues very-high.

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

*Describes the biological roles of HPSE2 (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:** HPSE2's established molecular role includes heparan sulfate proteoglycan binding.


### Pathways affected {#pathways}

HPSE2 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** heparan sulfate proteoglycan binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-15.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-15 |

## Associated conditions {#conditions}

[urofacial syndrome type 1](https://sugi.bio/atlas/disease/urofacial-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Urofacial syndrome type 1, HPSE2-Related Urofacial Syndrome.

## Similar variants {#similar}

Related HPSE2 variant pages (same residue, condition, or type): [HPSE2 p.Asn489fs](/variant/hpse2-p-asn489fs), [HPSE2 p.Asp84fs](/variant/hpse2-p-asp84fs), [HPSE2 p.Phe436fs](/variant/hpse2-p-phe436fs), [HPSE2 p.Thr370_Tyr371insTer](/variant/hpse2-p-thr370-tyr371inster), [HPSE2 p.Val382fs](/variant/hpse2-p-val382fs), [HPSE2 c.1099-1G>A](/variant/hpse2-c-1099-minus-1g-a), [HPSE2 c.291-1G>T](/variant/hpse2-c-291-minus-1g-t), [HPSE2 p.Ala20fs](/variant/hpse2-p-ala20fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3589444). 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.*