Is LRRK2 p.Phe348= (c.1044T>C) pathogenic?

LRRK2 p.Phe348= (c.1044T>C) is classified Likely benign in LRRK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-16). Ultra-rare (popmax 0.033%, mid); Associated with autosomal dominant Parkinson disease 8.

What condition is associated with LRRK2 p.Phe348= (c.1044T>C)?

LRRK2 p.Phe348= (c.1044T>C) is associated with autosomal dominant Parkinson disease 8 (ClinVar).

How common is LRRK2 p.Phe348= (c.1044T>C) in the general population?

LRRK2 p.Phe348= (c.1044T>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

LRRK2 p.Phe348=

c.1044T>C · rs2499503181 · VCV1775095

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

autosomal dominant Parkinson disease 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.036	GERP -3.2, phastCons 0.94
Overall
CADD	4.961	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000124% 2/1,613,890 alleles · ultra-rare exomes 2/1,461,544 · genomes 0/152,346 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LRRK2
Protein: p.Phe348=
Coding: c.1044T>C
MANE Select: NM_198578
dbSNP: rs2499503181
Type: single nucleotide variant
Location: chr12:40251317 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 58 PDB
Residue 348: an α-helix; the 'required for rab29-mediated activation' region

Full LRRK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant Parkinson disease 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

LRRK2 p.Arg1441Cys Pathogenic ★★ ⚠ same condition
LRRK2 p.Arg1441Gly Pathogenic ★★ ⚠ same condition
LRRK2 p.Arg1441His Pathogenic/Likely pathogenic ★★ ⚠ same condition
LRRK2 p.Ile2020Thr Pathogenic ★★ ⚠ same condition
LRRK2 c.1102-3C>T Uncertain significance ★★ same condition
LRRK2 c.2241+1G>A Uncertain significance ★★ same condition
LRRK2 c.7028+2T>C Uncertain significance ★★ same condition
LRRK2 p.Ala1151Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/lrrk2-p-phe348 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown