# NM_001084.5(PLOD3):c.1116G>A (p.Arg372=)

https://sugi.bio/variant/plod3-p-arg372

## Summary

**PLOD3 p.Arg372= (c.1116G>A)** is classified **Likely benign** in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PLOD3 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 | [PLOD3](https://sugi.bio/atlas/gene/PLOD3/) |
| Protein change (HGVS p.) | p.Arg372= |
| Coding change (HGVS c.) | c.1116G>A |
| MANE Select transcript | [NM_001084](https://www.ncbi.nlm.nih.gov/nuccore/NM_001084) |
| Variant type | single nucleotide variant |
| Location | chr7:101212264-101212264 (GRCh38) |
| ClinVar | [VCV3653359](https://www.ncbi.nlm.nih.gov/clinvar/variation/3653359/) |

**All HGVS expressions:** `NC_000007.13:g.100855545C>T`, `NC_000007.14:g.101212264C>T`, `NG_012148.1:g.10467G>A`, `NM_001084.5:c.1116G>A`

## 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 **donor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.746, GERP 1.26, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 10.3**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 11 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PLOD3** population constraint: LOEUF 0.925, pLI 1.6589e-17, missense-Z -0.055463; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **372** lies in the 'accessory region' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 91.80, 84% of residues very-high.

**18 experimental structure(s)** (PDB): [6FXK](https://www.rcsb.org/structure/6FXK), [6FXM](https://www.rcsb.org/structure/6FXM), [6FXR](https://www.rcsb.org/structure/6FXR), [6FXT](https://www.rcsb.org/structure/6FXT), [6FXX](https://www.rcsb.org/structure/6FXX), [6FXY](https://www.rcsb.org/structure/6FXY) — incl. mutant structure 6TEU.

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

*Describes the biological roles of PLOD3 (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:** PLOD3's established molecular role includes iron ion binding. p.Arg372= falls in the accessory region region.


### Pathways affected {#pathways}

PLOD3 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:** iron ion binding, procollagen-lysine 5-dioxygenase activity, procollagen glucosyltransferase activity, small molecule binding, metal ion binding, procollagen galactosyltransferase activity.

**Biological process:** collagen biosynthetic process, protein O-linked glycosylation via galactose.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-14.

**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 | 2024-05-14 |

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

## Similar variants {#similar}

Related PLOD3 variant pages (same residue, condition, or type): [PLOD3 c.1359-1G>C](/variant/plod3-c-1359-minus-1g-c), [PLOD3 p.Arg452Ter](/variant/plod3-p-arg452ter), [PLOD3 p.Tyr630Ter](/variant/plod3-p-tyr630ter), [PLOD3 c.338+6G>C](/variant/plod3-c-338-plus-6g-c), [PLOD3 p.Ala371Val](/variant/plod3-p-ala371val), [PLOD3 p.Ala431Thr](/variant/plod3-p-ala431thr), [PLOD3 p.Ala59Val](/variant/plod3-p-ala59val), [PLOD3 p.Ala646Val](/variant/plod3-p-ala646val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 3653359). 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.*