# NM_182943.3(PLOD2):c.893dup (p.Ser299fs)

https://sugi.bio/variant/plod2-p-ser299fs

## Summary

**PLOD2 p.Ser299fs (c.893dup)** is classified **Pathogenic** in PLOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-05). Very rare (popmax 8.52e-05%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs2473262415 · 1 submitter · very rare (popmax 8.52e-05%, nfe)

## For patients & families {#patients}

This is a change in the PLOD2 gene that is reported as disease-causing, but on limited review, 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 | [PLOD2](https://sugi.bio/atlas/gene/PLOD2/) |
| Protein change (HGVS p.) | p.Ser299fs |
| Coding change (HGVS c.) | c.893dup |
| MANE Select transcript | [NM_182943](https://www.ncbi.nlm.nih.gov/nuccore/NM_182943) |
| dbSNP | [rs2473262415](https://www.ncbi.nlm.nih.gov/snp/rs2473262415/) |
| Variant type | Duplication |
| Location | chr3:146088697-146088698 (GRCh38) |
| ClinVar | [VCV2826246](https://www.ncbi.nlm.nih.gov/clinvar/variation/2826246/) |

**All HGVS expressions:** `NC_000003.11:g.145806485dup`, `NC_000003.12:g.146088698dup`, `NG_009251.1:g.77798dup`, `NM_000935.3:c.893dup`, `NM_182943.3:c.893dup`

## 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 0.443, GERP -3.96, phastCons 0.999 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.209, pLI 6.8068e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 20**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.52e-05%** (nfe) · 1/1,174,088 in the highest group · 1/1,607,002 alleles overall — very rare (popmax 8.52e-05%, 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}

**PLOD2** population constraint: LOEUF 1.209, pLI 6.8068e-07, missense-Z 0.24827; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **299** lies in a UniProt-annotated variant site (in brks2; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 92.63, 88% of residues very-high.

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

*Describes the biological roles of PLOD2 (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:** PLOD2's established molecular role includes procollagen-lysine 5-dioxygenase activity.


### Pathways affected {#pathways}

PLOD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |

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

**Molecular function:** procollagen-lysine 5-dioxygenase activity.

**Biological process:** response to hypoxia, collagen biosynthetic process, obsolete hydroxylysine biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-05.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-05 |

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

## Similar variants {#similar}

Related PLOD2 variant pages (same residue, condition, or type): [PLOD2 p.Cys4fs](/variant/plod2-p-cys4fs), [PLOD2 p.Val523fs](/variant/plod2-p-val523fs), [PLOD2 c.339-22dup](/variant/plod2-c-339-minus-22dup), [PLOD2 p.Gly301fs](/variant/plod2-p-gly301fs), [PLOD2 p.Gly534fs](/variant/plod2-p-gly534fs), [PLOD2 p.Phe118fs](/variant/plod2-p-phe118fs), [PLOD2 p.Ser621_Gly622insSer](/variant/plod2-p-ser621-gly622insser), [PLOD2 c.1006-4dup](/variant/plod2-c-1006-minus-4dup).

### 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 2826246). 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.*