# NM_000312.4(PROC):c.1378_1379dup (p.Pro461fs)

https://sugi.bio/variant/proc-p-pro461fs

## Summary

**PROC p.Pro461fs (c.1378_1379dup)** is classified **Likely pathogenic** in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). No gnomAD frequency available for this variant; Associated with Reduced protein C activity.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1573462001 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PROC gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Reduced protein C activity.

*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 | [PROC](https://sugi.bio/atlas/gene/PROC/) |
| Protein change (HGVS p.) | p.Pro461fs |
| Coding change (HGVS c.) | c.1378_1379dup |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs1573462001](https://www.ncbi.nlm.nih.gov/snp/rs1573462001/) |
| Variant type | Duplication |
| Location | chr2:127428937-127428938 (GRCh38) |
| ClinVar | [VCV626997](https://www.ncbi.nlm.nih.gov/clinvar/variation/626997/) |

**All HGVS expressions:** `LRG_599:g.15519_15520dup`, `NC_000002.11:g.128186514_128186515dup`, `NC_000002.12:g.127428938_127428939dup`, `NG_016323.1:g.15519_15520dup`, `NM_000312.3:c.1378_1379dupGC`, `NM_000312.4:c.1378_1379dup`, `NM_001375602.1:c.1561_1562dup`, `NM_001375603.1:c.1543_1544dup`, `NM_001375604.1:c.1441_1442dup`, `NM_001375605.1:c.1480_1481dup`, `NM_001375606.1:c.1546_1547dup`, `NM_001375607.1:c.1564_1565dup`, `NM_001375608.1:c.1321_1322dup`, `NM_001375609.1:c.1354_1355dup`, `NM_001375610.1:c.1372_1373dup`, `NM_001375611.1:c.1378_1379dup`, `NM_001375613.1:c.1378_1379dup`

## 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 0.616, GERP -1.47 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.894, pLI 2.1926e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (9 of 9)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PROC** population constraint: LOEUF 0.894, pLI 2.1926e-05, missense-Z 1.6178. *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 thrombophilia due to congenital protein C deficiency** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.35, 58% of residues very-high.

**12 experimental structure(s)** (PDB): [1AUT](https://www.rcsb.org/structure/1AUT), [1LQV](https://www.rcsb.org/structure/1LQV), [3F6U](https://www.rcsb.org/structure/3F6U), [3JTC](https://www.rcsb.org/structure/3JTC), [4DT7](https://www.rcsb.org/structure/4DT7), [6M3B](https://www.rcsb.org/structure/6M3B).

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

*Describes the biological roles of PROC (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:** PROC's established molecular role includes serine-type endopeptidase activity. In Reactome, PROC is annotated in disease pathway(s) including **Defective cleavage of FV variant at R334**, **Defective cleavage of FV variant at a.a.534 **.

**Disease mechanism (Reactome):** PROC loss or alteration is curated in [Defective cleavage of FV variant at R334](https://reactome.org/content/detail/R-HSA-9930479), [Defective cleavage of FV variant at a.a.534 ](https://reactome.org/content/detail/R-HSA-9930449).

### Pathways affected {#pathways}

PROC participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective cleavage of FV variant at R334](https://reactome.org/content/detail/R-HSA-9930479) | curated |
| ⚕ [Defective cleavage of FV variant at a.a.534 ](https://reactome.org/content/detail/R-HSA-9930449) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Fibrin formation](https://reactome.org/content/detail/R-HSA-9769733) | curated |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

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

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

**Biological process:** negative regulation of apoptotic process, negative regulation of inflammatory response, negative regulation of coagulation, positive regulation of establishment of endothelial barrier.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-02-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | criteria provided, single submitter | research | 2019-02-01 |

## Associated conditions {#conditions}

[Reduced protein C activity](https://sugi.bio/atlas/disease/reduced-protein-c-activity/).

**Reported phenotype names (ClinVar):** Reduced protein C activity.

## Similar variants {#similar}

Related PROC variant pages (same residue, condition, or type): [PROC p.Ala178Pro](/variant/proc-p-ala178pro), [PROC p.Cys147Tyr](/variant/proc-p-cys147tyr), [PROC c.797-2A>T](/variant/proc-c-797-minus-2a-t), [PROC p.Lys457fs](/variant/proc-p-lys457fs), [PROC p.Ser141Pro](/variant/proc-p-ser141pro), [PROC p.Thr340Lys](/variant/proc-p-thr340lys), [PROC p.Trp444Ter](/variant/proc-p-trp444ter), [PROC p.Val26Met](/variant/proc-p-val26met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 626997). 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.*