# NM_182943.3(PLOD2):c.1582T>C (p.Ser528Pro)

https://sugi.bio/variant/plod2-p-ser528pro

## Summary

**PLOD2 p.Ser528Pro (c.1582T>C)** is classified **Uncertain significance** in PLOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.9656); Very rare (popmax 0.0017%, nfe).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1936362271 · 2 submitters · AlphaMissense likely pathogenic · very rare (popmax 0.0017%, nfe)

## For patients & families {#patients}

This is a change in the PLOD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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.Ser528Pro |
| Coding change (HGVS c.) | c.1582T>C |
| MANE Select transcript | [NM_182943](https://www.ncbi.nlm.nih.gov/nuccore/NM_182943) |
| dbSNP | [rs1936362271](https://www.ncbi.nlm.nih.gov/snp/rs1936362271/) |
| Variant type | single nucleotide variant |
| Location | chr3:146076877-146076877 (GRCh38) |
| ClinVar | [VCV2419642](https://www.ncbi.nlm.nih.gov/clinvar/variation/2419642/) |

**All HGVS expressions:** `NC_000003.11:g.145794664A>G`, `NC_000003.12:g.146076877A>G`, `NG_009251.1:g.89619T>C`, `NM_000935.3:c.1519T>C`, `NM_182943.3:c.1582T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9656)
- REVEL 0.653 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.778 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.107, GERP -0.938, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S507P** vs ClinVar **S528P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.6**. 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 0.99** across the covering region of the MANE Select transcript (146,070,720–146,160,989), spanning 90,269 bp. Chi-square p 0.85. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain, 18 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 **0.0017%** (nfe) · FAF95 0.00109% · FAF99 0.000877% · 19/1,116,386 in the highest group · 19/1,542,956 alleles overall — very rare (popmax 0.0017%, 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 **507** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-23.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-23 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-17 |

**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 2026-10-14); 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 2419642). 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.*