# NM_000312.4(PROC):c.125G>A (p.Arg42His)

https://sugi.bio/variant/proc-p-arg42his

## Summary

**PROC p.Arg42His (c.125G>A)** is classified **Likely pathogenic** in PROC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-14). AlphaMissense: likely benign (0.3198); Very rare (popmax 0.000424%, nfe); Associated with Deep venous thrombosis.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs369504169 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000424%, nfe)

## 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 Deep venous thrombosis.

*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.Arg42His |
| Coding change (HGVS c.) | c.125G>A |
| MANE Select transcript | [NM_000312](https://www.ncbi.nlm.nih.gov/nuccore/NM_000312) |
| dbSNP | [rs369504169](https://www.ncbi.nlm.nih.gov/snp/rs369504169/) |
| Variant type | single nucleotide variant |
| Location | chr2:127421337-127421337 (GRCh38) |
| ClinVar | [VCV161333](https://www.ncbi.nlm.nih.gov/clinvar/variation/161333/) |

**All HGVS expressions:** `LRG_599:g.7918G>A`, `LRG_599t1:c.125G>A`, `NC_000002.11:g.128178913G>A`, `NC_000002.12:g.127421337G>A`, `NG_016323.1:g.7918G>A`, `NM_000312.4:c.125G>A`, `NM_001375602.1:c.308G>A`, `NM_001375603.1:c.188G>A`, `NM_001375604.1:c.188G>A`, `NM_001375605.1:c.125G>A`, `NM_001375606.1:c.188G>A`, `NM_001375607.1:c.209G>A`, `NM_001375608.1:c.125G>A`, `NM_001375609.1:c.101G>A`, `NM_001375610.1:c.119G>A`, `NM_001375611.1:c.125G>A`, `NM_001375613.1:c.125G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3198) — ⚠ discordant with the pathogenic call
- REVEL 0.928 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -12.11 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.529, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.3**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PROC (560 scored positions, the nearest 4 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,920 in the highest group · 7/1,613,762 alleles overall — very rare (popmax 0.000424%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,232 |
| European (non-Finnish) (grpmax) | 0.000424% | 235,984 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **42** lies in a UniProt-annotated variant site (in patients with proc deficiency); a UniProt-annotated variant site (in malakoff; low anticoagulant activity); a UniProt-annotated variant site (in thph3; type ii; osaka-10; alters proteolytic processing so that s-42 is the n-terminus of the mature 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-14.

**Submitter consensus:** unanimous (4/4 Likely pathogenic).

**Submission history:** 4 submissions (2014–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CSER _CC_NCGL, University of Washington | Likely pathogenic | no assertion criteria provided | research | 2014-06-01 |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | criteria provided, single submitter | research | 2019-02-01 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-14 |

## Associated conditions {#conditions}

[Deep venous thrombosis](https://sugi.bio/atlas/disease/deep-venous-thrombosis/), [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):** Deep venous thrombosis, Thrombophilia due to protein C deficiency, autosomal dominant, Thromboembolism, not provided, Deep vein thrombosis, PROC DEFICIENCY, AUTOSOMAL DOMINANT, PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT, none provided.

## Same-residue context {#hotspot}

Residue **42** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [PROC p.Arg42Leu](/variant/proc-p-arg42leu), [PROC p.Arg42Cys](/variant/proc-p-arg42cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PROC variant pages (same residue, condition, or type): [PROC p.Arg42Cys](/variant/proc-p-arg42cys), [PROC p.Arg42Leu](/variant/proc-p-arg42leu), [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 2026-10-15); 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 161333). 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.*