# NM_000312.4(PROC):c.94C>T (p.Arg32Cys)

https://sugi.bio/variant/proc-p-arg32cys

## Summary

**PROC p.Arg32Cys (c.94C>T)** is classified **Pathogenic** in PROC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1636); Very rare (popmax 0.0011%, sas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2468324848 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the PROC gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 2 submitters, and is linked to thrombophilia due to protein C deficiency, autosomal dominant.

*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) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | PROC is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Severe hereditary thrombophilia due to congenital protein C deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thin skin — Frequent (79-30%)
- Purpura — Frequent (79-30%)
- Venous thrombosis — Frequent (79-30%)
- Aplasia/Hypoplasia of the skin — Frequent (79-30%)
- Abnormality of skin pigmentation — Occasional (29-5%)
- Warfarin-induced skin necrosis — Occasional (29-5%)
- Pulmonary embolism — Occasional (29-5%)
- Venous insufficiency — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018574/index) · [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.Arg32Cys |
| Coding change (HGVS c.) | c.94C>T |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs2468324848](https://www.ncbi.nlm.nih.gov/snp/rs2468324848/) |
| Variant type | single nucleotide variant |
| Location | chr2:127421306-127421306 (GRCh38) |
| ClinVar | [VCV1992373](https://www.ncbi.nlm.nih.gov/clinvar/variation/1992373/) |

**All HGVS expressions:** `LRG_599:g.7887C>T`, `LRG_599t1:c.94C>T`, `NC_000002.11:g.128178882C>T`, `NC_000002.12:g.127421306C>T`, `NG_016323.1:g.7887C>T`, `NM_000312.4:c.94C>T`, `NM_001375602.1:c.277C>T`, `NM_001375603.1:c.157C>T`, `NM_001375604.1:c.157C>T`, `NM_001375605.1:c.94C>T`, `NM_001375606.1:c.157C>T`, `NM_001375607.1:c.190-12C>T`, `NM_001375608.1:c.94C>T`, `NM_001375609.1:c.70C>T`, `NM_001375610.1:c.88C>T`, `NM_001375611.1:c.94C>T`, `NM_001375613.1:c.94C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1636) — ⚠ discordant with the pathogenic call
- REVEL 0.597 (indeterminate)
- SaProt LLR -9.223 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.43) — consistent with the pathogenic call
- CADD: **PHRED 25.0**. 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 0.84** across the covering region of the MANE Select transcript (127,419,943–127,428,943), spanning 9,000 bp. Chi-square p 3.6e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.14**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.13. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000292% · FAF99 0.000211% · 1/91,074 in the highest group · 9/1,461,498 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,074 |
| European (non-Finnish) | 0.000678% | 147,486 |

*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}

Residue **32** lies in an α-helix; a UniProt-annotated variant site (in thph3).

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-22.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| MVZ Martinsried, Medicover Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-04-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-22 |

## Associated conditions {#conditions}

[thrombophilia due to protein C deficiency, autosomal dominant](https://sugi.bio/atlas/disease/thrombophilia-due-to-protein-c-deficiency-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Thrombophilia due to protein C deficiency, autosomal dominant, PROC DEFICIENCY, AUTOSOMAL DOMINANT, PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT.

## Similar variants {#similar}

Related PROC variant pages (same residue, condition, or type): [PROC p.Arg32=](/variant/proc-p-arg32), [PROC p.Arg32His](/variant/proc-p-arg32his), [PROC p.Ala309Thr](/variant/proc-p-ala309thr), [PROC p.Arg199Ter](/variant/proc-p-arg199ter), [PROC p.Arg211Gln](/variant/proc-p-arg211gln), [PROC p.Arg211Trp](/variant/proc-p-arg211trp), [PROC p.Arg220Gln](/variant/proc-p-arg220gln), [PROC p.Arg220Trp](/variant/proc-p-arg220trp).

### 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 2026-07-14); 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 1992373). 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.*