# NM_000062.3(SERPING1):c.329_341del (p.Pro110fs)

https://sugi.bio/variant/serping1-p-pro110fs

## Summary

**SERPING1 p.Pro110fs (c.329_341del)** is classified **Pathogenic** in SERPING1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-27). Associated with hereditary angioedema type 1.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SERPING1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hereditary angioedema 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SERPING1 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hereditary angioedema with C1Inh deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Facial edema — Frequent (79-30%)
- Skin rash — Frequent (79-30%)
- Joint swelling — Frequent (79-30%)
- Diarrhea — Frequent (79-30%)
- Nausea and vomiting — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Pharyngeal edema — Frequent (79-30%)
- Laryngeal edema — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016933/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SERPING1](https://sugi.bio/atlas/gene/SERPING1/) |
| Protein change (HGVS p.) | p.Pro110fs |
| Coding change (HGVS c.) | c.329_341del |
| MANE Select transcript | [NM_000062](https://www.ncbi.nlm.nih.gov/nuccore/NM_000062) |
| Variant type | Deletion |
| Location | chr11:57600152-57600164 (GRCh38) |
| ClinVar | [VCV4291107](https://www.ncbi.nlm.nih.gov/clinvar/variation/4291107/) |

**All HGVS expressions:** `LRG_105:g.7603_7615del`, `LRG_105t1:c.329_341del`, `NC_000011.10:g.57600156_57600168del`, `NC_000011.9:g.57367629_57367641del`, `NG_009625.1:g.7603_7615del`, `NM_000062.3:c.329_341del`, `NM_001032295.2:c.329_341del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 0.318, GERP -0.804, phastCons 0.002 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.278, pLI 0.99999), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 8**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**SERPING1** population constraint: LOEUF 0.278, pLI 0.99999, missense-Z 1.8596. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary angioedema with C1Inh deficiency** — Definitive (AD)

## Protein context {#protein}

Residue **110** lies in the 'disordered' region; the '7 x 4 aa tandem repeats of [qe]-p-t-[tq]' region; a UniProt-annotated variant site (in hae1; phenotype consistent with hereditary angioedema type 2).

AlphaFold model confidence (whole protein): pLDDT 80.63, 68% of residues very-high.

**5 experimental structure(s)** (PDB): [2OAY](https://www.rcsb.org/structure/2OAY), [5DU3](https://www.rcsb.org/structure/5DU3), [5DUQ](https://www.rcsb.org/structure/5DUQ), [7AKV](https://www.rcsb.org/structure/7AKV), [8W18](https://www.rcsb.org/structure/8W18).

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

*Describes the biological roles of SERPING1 (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:** SERPING1's established molecular role includes serine-type endopeptidase inhibitor activity. p.Pro110fs falls in the disordered region. In Reactome, SERPING1 is annotated in disease pathway(s) including **Defective SERPING1 causes hereditary angioedema**.

**Disease mechanism (Reactome):** SERPING1 loss or alteration is curated in [Defective SERPING1 causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657689).

### Pathways affected {#pathways}

SERPING1 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective SERPING1 causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657689) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Regulation of FXIIa and plasma kallikrein activity](https://reactome.org/content/detail/R-HSA-9855719) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Molecular function:** serine-type endopeptidase inhibitor activity.

**Biological process:** negative regulation of complement activation, lectin pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-07-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2026-07-27 |

## Associated conditions {#conditions}

[hereditary angioedema type 1](https://sugi.bio/atlas/disease/hereditary-angioedema-type-1/).

**Reported phenotype names (ClinVar):** Hereditary angioedema type 1.

## Similar variants {#similar}

Related SERPING1 variant pages (same residue, condition, or type): [SERPING1 p.Pro110=](/variant/serping1-p-pro110), [SERPING1 p.Leu386fs](/variant/serping1-p-leu386fs), [SERPING1 p.Phe55fs](/variant/serping1-p-phe55fs), [SERPING1 p.Ser283fs](/variant/serping1-p-ser283fs), [SERPING1 c.1029+1del](/variant/serping1-c-1029-plus-1del), [SERPING1 c.1030delG](/variant/serping1-c-1030delg), [SERPING1 c.685+1del](/variant/serping1-c-685-plus-1del), [SERPING1 c.990_1029+16del](/variant/serping1-c-990-1029-plus-16del).

### 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 4291107). 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.*