# NM_198578.4(LRRK2):c.3207C>T (p.Asp1069=)

https://sugi.bio/variant/lrrk2-p-asp1069

## Summary

**LRRK2 p.Asp1069= (c.3207C>T)** is classified **Likely benign** in LRRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · rsID rs2499745799 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the LRRK2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [LRRK2](https://sugi.bio/atlas/gene/LRRK2/) |
| Protein change (HGVS p.) | p.Asp1069= |
| Coding change (HGVS c.) | c.3207C>T |
| MANE Select transcript | [NM_198578](https://www.ncbi.nlm.nih.gov/nuccore/NM_198578) |
| dbSNP | [rs2499745799](https://www.ncbi.nlm.nih.gov/snp/rs2499745799/) |
| Variant type | single nucleotide variant |
| Location | chr12:40298353-40298353 (GRCh38) |
| ClinVar | [VCV3229598](https://www.ncbi.nlm.nih.gov/clinvar/variation/3229598/) |

**All HGVS expressions:** `NC_000012.11:g.40692155C>T`, `NC_000012.12:g.40298353C>T`, `NG_011709.1:g.78343C>T`, `NG_011709.2:g.78358C>T`, `NM_198578.4:c.3207C>T`

## 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 0.483, GERP -0.056, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 8.661**. 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 (C>G, Δ0.20 acceptor loss), 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: **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}

**LRRK2** population constraint: LOEUF 0.778, pLI 1.0562e-40, missense-Z 1.6639; ClinGen dosage — haploinsufficiency dosage-sensitivity unlikely, triplosensitivity 0/3. *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):

- **Parkinson disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.64, 13% of residues very-high.

**58 experimental structure(s)** (PDB): [2ZEJ](https://www.rcsb.org/structure/2ZEJ), [3D6T](https://www.rcsb.org/structure/3D6T), [5MY9](https://www.rcsb.org/structure/5MY9), [5MYC](https://www.rcsb.org/structure/5MYC), [6DLO](https://www.rcsb.org/structure/6DLO), [6DLP](https://www.rcsb.org/structure/6DLP) — incl. mutant structure 7LI3.

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

*Describes the biological roles of LRRK2 (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:** LRRK2's established molecular role includes SNARE binding.


### Pathways affected {#pathways}

LRRK2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PTK6 promotes HIF1A stabilization](https://reactome.org/content/detail/R-HSA-8857538) | curated |

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

**Molecular function:** SNARE binding, magnesium ion binding, actin binding, GTPase activity, protein kinase activity, protein serine/threonine kinase activity.

**Biological process:** MAPK cascade, protein phosphorylation, endocytosis, response to oxidative stress, mitochondrion organization, endoplasmic reticulum organization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related LRRK2 variant pages (same residue, condition, or type): [LRRK2 p.Ala1396Ser](/variant/lrrk2-p-ala1396ser), [LRRK2 p.Ala1413Glu](/variant/lrrk2-p-ala1413glu), [LRRK2 p.Ala1430Val](/variant/lrrk2-p-ala1430val), [LRRK2 p.Ala1440Val](/variant/lrrk2-p-ala1440val), [LRRK2 p.Ala1572Thr](/variant/lrrk2-p-ala1572thr), [LRRK2 p.Ala1659Gly](/variant/lrrk2-p-ala1659gly), [LRRK2 p.Ala233Val](/variant/lrrk2-p-ala233val), [LRRK2 p.Ala417Val](/variant/lrrk2-p-ala417val).

### 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 3229598). 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.*