Is LIPA p.Arg218= (c.654A>G) pathogenic?

LIPA p.Arg218= (c.654A>G) is classified Likely benign in LIPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-13). Ultra-rare (popmax 0.0254%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LIPA p.Arg218= (c.654A>G)?

LIPA p.Arg218= (c.654A>G) is associated with Cardiovascular phenotype, Wolman disease (ClinVar).

How common is LIPA p.Arg218= (c.654A>G) in the general population?

LIPA p.Arg218= (c.654A>G) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

LIPA p.Arg218=

c.654A>G · rs773232583 · VCV1127911

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.7	GERP -3.9
Overall
CADD	0.259	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,900 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00118% 19/1,614,006 alleles · ultra-rare exomes 9/1,461,856 · genomes 10/152,150 · 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: LIPA
Protein: p.Arg218=
Coding: c.654A>G
MANE Select: NM_000235
dbSNP: rs773232583
Type: single nucleotide variant
Location: chr10:89225113 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wolman disease

Similar variants

LIPA p.Arg218Ter Pathogenic ★★ same residue
LIPA p.Arg218Gln Uncertain significance ★ ⚠ same residue
LIPA c.111+1G>A Pathogenic/Likely pathogenic ★★ same condition
LIPA c.539-2A>G Pathogenic ★★ same condition
LIPA c.675+2T>G Likely pathogenic ★★ same condition
LIPA c.676-2A>T Pathogenic ★★ same condition
LIPA c.822+1G>A Likely pathogenic ★★ same condition
LIPA c.823-2A>G Likely pathogenic ★★ 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/lipa-p-arg218 (accessed [today's date]).

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