# NM_000301.5(PLG):c.2022T>C (p.Pro674=)

https://sugi.bio/variant/plg-p-pro674

## Summary

**PLG p.Pro674= (c.2022T>C)** is classified **Likely benign** in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). Very rare (popmax 0.00155%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.00155%, nfe)

## For patients & families {#patients}

This is a change in the PLG gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [PLG](https://sugi.bio/atlas/gene/PLG/) |
| Protein change (HGVS p.) | p.Pro674= |
| Coding change (HGVS c.) | c.2022T>C |
| MANE Select transcript | [NM_000301](https://www.ncbi.nlm.nih.gov/nuccore/NM_000301) |
| Variant type | single nucleotide variant |
| Location | chr6:160741314-160741314 (GRCh38) |
| ClinVar | [VCV4771890](https://www.ncbi.nlm.nih.gov/clinvar/variation/4771890/) |

**All HGVS expressions:** `LRG_571:g.44122T>C`, `LRG_571t1:c.2022T>C`, `NC_000006.11:g.161162346T>C`, `NC_000006.12:g.160741314T>C`, `NG_016200.1:g.44122T>C`, `NM_000301.5:c.2022T>C`

## 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 -7.465, GERP -0.789 — fast-evolving / accelerated position
- CADD: **PHRED 1.36**. 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 (T>A, Δ0.70 acceptor gain), 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 **0.00155%** (nfe) · FAF95 0.000971% · FAF99 0.000801% · 18/1,158,166 in the highest group · 19/1,590,292 alleles overall — very rare (popmax 0.00155%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00155% | 64,343 |
| South Asian | 0.0011% | 90,638 |

*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}

**PLG** population constraint: LOEUF 0.559, pLI 0.16673, missense-Z 1.5082. *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):

- **hypoplasminogenemia** — Definitive (AR)

## Protein context {#protein}

Residue **674** lies in the peptidase s1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 83.53, 46% of residues very-high.

**49 experimental structure(s)** (PDB): [1B2I](https://www.rcsb.org/structure/1B2I), [1BML](https://www.rcsb.org/structure/1BML), [1BUI](https://www.rcsb.org/structure/1BUI), [1CEA](https://www.rcsb.org/structure/1CEA), [1CEB](https://www.rcsb.org/structure/1CEB), [1DDJ](https://www.rcsb.org/structure/1DDJ) — incl. mutant structure 1RJX.

## What this gene does {#gene-function}

*Describes the biological roles of PLG (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:** PLG's established molecular role includes protease binding. p.Pro674= falls in the peptidase s1 domain.


### Pathways affected {#pathways}

PLG participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |
| [Dissolution of Fibrin Clot](https://reactome.org/content/detail/R-HSA-75205) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | 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 |
| [Signaling by PDGF](https://reactome.org/content/detail/R-HSA-186797) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, endopeptidase activity, serine-type endopeptidase activity, signaling receptor binding, enzyme binding, kinase binding.

**Biological process:** proteolysis, blood coagulation, negative regulation of cell-substrate adhesion, extracellular matrix disassembly, collagen catabolic process, fibrinolysis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PLG variant pages (same residue, condition, or type): [PLG p.Lys330Glu](/variant/plg-p-lys330glu), [PLG p.Lys38Glu](/variant/plg-p-lys38glu), [PLG c.2271+5G>A](/variant/plg-c-2271-plus-5g-a), [PLG c.669-3C>G](/variant/plg-c-669-minus-3c-g), [PLG p.Ala216Thr](/variant/plg-p-ala216thr), [PLG p.Ala459Val](/variant/plg-p-ala459val), [PLG p.Ala494Glu](/variant/plg-p-ala494glu), [PLG p.Ala507Val](/variant/plg-p-ala507val).

### 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 4771890). 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.*