# NM_182943.3(PLOD2):c.1614C>G (p.Ser538=)

https://sugi.bio/variant/plod2-p-ser538

## Summary

**PLOD2 p.Ser538= (c.1614C>G)** is classified **Likely benign** in PLOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). Ultra-rare (popmax 0.0134%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0134%, amr)

## For patients & families {#patients}

This is a change in the PLOD2 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 | [PLOD2](https://sugi.bio/atlas/gene/PLOD2/) |
| Protein change (HGVS p.) | p.Ser538= |
| Coding change (HGVS c.) | c.1614C>G |
| MANE Select transcript | [NM_182943](https://www.ncbi.nlm.nih.gov/nuccore/NM_182943) |
| Variant type | single nucleotide variant |
| Location | chr3:146076845-146076845 (GRCh38) |
| ClinVar | [VCV4745183](https://www.ncbi.nlm.nih.gov/clinvar/variation/4745183/) |

**All HGVS expressions:** `NC_000003.11:g.145794632G>C`, `NC_000003.12:g.146076845G>C`, `NG_009251.1:g.89651C>G`, `NM_000935.3:c.1551C>G`, `NM_182943.3:c.1614C>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.28) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.357, GERP -3.8, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 2.835**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.28**, donor gain **0.00**. Largest is acceptor gain, 50 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0134%** (amr) · FAF95 0.00666% · FAF99 0.00486% · 8/59,532 in the highest group · 8/1,591,300 alleles overall — ultra-rare (popmax 0.0134%, amr).

*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 **538** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-29.

**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 | 2025-10-29 |

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

## Similar variants {#similar}

Related PLOD2 variant pages (same residue, condition, or type): [PLOD2 c.1500+1G>T](/variant/plod2-c-1500-plus-1g-t), [PLOD2 p.Arg440Ter](/variant/plod2-p-arg440ter), [PLOD2 p.Arg473Ter](/variant/plod2-p-arg473ter), [PLOD2 p.Arg495Ter](/variant/plod2-p-arg495ter), [PLOD2 p.Arg680Ter](/variant/plod2-p-arg680ter), [PLOD2 c.1232+5T>A](/variant/plod2-c-1232-plus-5t-a), [PLOD2 c.-170C>G](/variant/plod2-c-minus-170c-g), [PLOD2 p.Ala415Val](/variant/plod2-p-ala415val).

### 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 4745183). 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.*