# NM_000312.4(PROC):c.541T>G (p.Phe181Val)

https://sugi.bio/variant/proc-p-phe181val

## Summary

**PROC p.Phe181Val (c.541T>G)** is classified **Pathogenic/Likely pathogenic** in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-27). AlphaMissense: ambiguous (0.4146); Ultra-rare (popmax 0.0601%, eas); Associated with thrombophilia due to protein C deficiency, autosomal dominant.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs199469470 · 4 submitters · 2 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0601%, eas)

## For patients & families {#patients}

This is a change in the PROC gene that is considered likely disease-causing, submitted by 4 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.Phe181Val |
| Coding change (HGVS c.) | c.541T>G |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs199469470](https://www.ncbi.nlm.nih.gov/snp/rs199469470/) |
| Variant type | single nucleotide variant |
| Location | chr2:127426090-127426090 (GRCh38) |
| ClinVar | [VCV1394296](https://www.ncbi.nlm.nih.gov/clinvar/variation/1394296/) |

**All HGVS expressions:** `LRG_599:g.12671T>G`, `NC_000002.11:g.128183666T>G`, `NC_000002.12:g.127426090T>G`, `NG_016323.1:g.12671T>G`, `NM_000312.3:c.541T>G`, `NM_000312.4:c.541T>G`, `NM_001375602.1:c.724T>G`, `NM_001375603.1:c.706T>G`, `NM_001375604.1:c.604T>G`, `NM_001375605.1:c.643T>G`, `NM_001375606.1:c.709T>G`, `NM_001375607.1:c.727T>G`, `NM_001375608.1:c.484T>G`, `NM_001375609.1:c.517T>G`, `NM_001375610.1:c.535T>G`, `NM_001375611.1:c.541T>G`, `NM_001375613.1:c.541T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4146) — no call either way
- REVEL 0.675 (pathogenic-leaning)
- SaProt LLR -4.888 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.40) — consistent with the pathogenic call
- Conservation: phyloP 7.265, phastCons 1 — highly conserved
- CADD: **PHRED 26.0**. 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 **0.04**, donor loss **0.00**, acceptor gain **0.40**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.40**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0601%** (eas) · FAF95 0.0424% · FAF99 0.0365% · 27/44,888 in the highest group · 27/1,613,916 alleles overall — ultra-rare (popmax 0.0601%, eas).

*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 **181** lies in a β-strand; 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. 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-27.

**Submitter consensus:** conflicting (2 Pathogenic, 2 Likely pathogenic).

**Submission history:** 4 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-26 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-27 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-27 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[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):** Thrombophilia due to protein C deficiency, autosomal dominant, Thrombophilia due to protein C deficiency, autosomal recessive, not provided, PROC DEFICIENCY, AUTOSOMAL DOMINANT, PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT, PROC DEFICIENCY, AUTOSOMAL RECESSIVE, PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE, none provided.

## Similar variants {#similar}

Related PROC variant pages (same residue, condition, or type): [PROC p.Phe181Leu](/variant/proc-p-phe181leu), [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).

### 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 1394296). 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.*