# NM_000312.4(PROC):c.30C>T (p.Phe10=)

https://sugi.bio/variant/proc-p-phe10

## Summary

**PROC p.Phe10= (c.30C>T)** is classified **Conflicting classifications of pathogenicity** in PROC (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-04-01). Rare (popmax 0.576%, amr); Associated with thrombophilia due to protein C deficiency, autosomal recessive.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs148490199 · 7 submitters · 2 linked conditions · rare (popmax 0.576%, amr)

## For patients & families {#patients}

This is a change in the PROC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to thrombophilia due to protein C deficiency, autosomal recessive.

*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/0013041/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.Phe10= |
| Coding change (HGVS c.) | c.30C>T |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs148490199](https://www.ncbi.nlm.nih.gov/snp/rs148490199/) |
| Variant type | single nucleotide variant |
| Location | chr2:127419972-127419972 (GRCh38) |
| ClinVar | [VCV469121](https://www.ncbi.nlm.nih.gov/clinvar/variation/469121/) |

**All HGVS expressions:** `LRG_599:g.6553C>T`, `LRG_599t1:c.30C>T`, `NC_000002.11:g.128177548C>T`, `NC_000002.12:g.127419972C>T`, `NG_016323.1:g.6553C>T`, `NM_000312.4:c.30C>T`, `NM_001375602.1:c.213C>T`, `NM_001375603.1:c.93C>T`, `NM_001375604.1:c.93C>T`, `NM_001375605.1:c.30C>T`, `NM_001375606.1:c.93C>T`, `NM_001375607.1:c.149C>T`, `NM_001375608.1:c.30C>T`, `NM_001375609.1:c.47-1311C>T`, `NM_001375610.1:c.30C>T`, `NM_001375611.1:c.30C>T`, `NM_001375613.1:c.30C>T`

## 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 -0.671, GERP -0.908 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.151**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.38 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.576%** (amr) · FAF95 0.526% · FAF99 0.507% · 346/60,024 in the highest group · 409/1,613,872 alleles overall — rare (popmax 0.576%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.576% | 173 |
| African / African-American | 0.0373% | 2,680 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,462 |
| South Asian | 0.0022% | 45,529 |
| European (non-Finnish) | 0.00161% | 62,106 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-01.

**Submitter consensus:** conflicting (3 Uncertain significance, 3 Likely benign, 1 Benign).

**Submission history:** 7 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-03 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-28 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |

## Associated conditions {#conditions}

[thrombophilia due to protein C deficiency, autosomal recessive](https://sugi.bio/atlas/disease/thrombophilia-due-to-protein-c-deficiency-autosomal-recessive/), [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 recessive, Thrombophilia due to protein C deficiency, autosomal dominant, not provided, PROC-related disorder, PROC-related condition, none provided, PROC DEFICIENCY, AUTOSOMAL RECESSIVE, PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE, PROC DEFICIENCY, AUTOSOMAL DOMINANT, PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT.

## Similar variants {#similar}

Related PROC variant pages (same residue, condition, or type): [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), [PROC p.Arg271Trp](/variant/proc-p-arg271trp), [PROC p.Arg272Cys](/variant/proc-p-arg272cys).

### 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 469121). 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.*