# NM_000312.4(PROC):c.793C>T (p.Leu265Phe)

https://sugi.bio/variant/proc-p-leu265phe

## Summary

**PROC p.Leu265Phe (c.793C>T)** is classified **Conflicting classifications of pathogenicity** in PROC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-12-08). AlphaMissense: likely benign (0.3365); Very rare (popmax 0.00017%, nfe); Associated with PROC-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs121918156 · 5 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## 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 5 submitters, and is linked to PROC-related disorder.

*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.Leu265Phe |
| Coding change (HGVS c.) | c.793C>T |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs121918156](https://www.ncbi.nlm.nih.gov/snp/rs121918156/) |
| Variant type | single nucleotide variant |
| Location | chr2:127427219-127427219 (GRCh38) |
| ClinVar | [VCV675](https://www.ncbi.nlm.nih.gov/clinvar/variation/675/) |

**All HGVS expressions:** `LRG_599:g.13800C>T`, `LRG_599t1:c.793C>T`, `NC_000002.11:g.128184795C>T`, `NC_000002.12:g.127427219C>T`, `NG_016323.1:g.13800C>T`, `NM_000312.4:c.793C>T`, `NM_001375602.1:c.976C>T`, `NM_001375603.1:c.958C>T`, `NM_001375604.1:c.856C>T`, `NM_001375605.1:c.895C>T`, `NM_001375606.1:c.961C>T`, `NM_001375607.1:c.979C>T`, `NM_001375608.1:c.736C>T`, `NM_001375609.1:c.769C>T`, `NM_001375610.1:c.787C>T`, `NM_001375611.1:c.793C>T`, `NM_001375613.1:c.793C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3365)
- REVEL 0.76 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.435 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **donor gain** (Δ 0.98) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.645, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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 **0.00**, donor loss **0.61**, acceptor gain **0.00**, donor gain **0.98**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.61**, acceptor gain **0.00**, donor gain **0.98**.
- Pangolin: Δ**0.77** (gain), gain 0.77 / loss 0.68. 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,464 in the highest group · 2/1,612,152 alleles overall — very rare (popmax 0.00017%, nfe).

*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 **265** lies in a β-strand; the peptidase s1 domain; a UniProt-annotated variant site (in patients with proc deficiency).

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. p.Leu265Phe falls in the peptidase s1 domain. 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 2023-12-08.

**Submitter consensus:** conflicting (4 Likely pathogenic, 1 Pathogenic, 1 Uncertain significance).

**Submission history:** 6 submissions (1993–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1993-11-15 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | criteria provided, single submitter | research | 2019-02-01 |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-08 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** PROC-related disorder, Thrombophilia due to protein C deficiency, autosomal recessive, Deep venous thrombosis, Reduced protein C activity, Thrombophilia due to protein C deficiency, autosomal dominant, PROC-related condition, Deep vein thrombosis, PROC DEFICIENCY, AUTOSOMAL RECESSIVE, PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE, PROC 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 2026-10-14); 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 675). 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.*