Is LIPA p.Ile252= (c.756A>C) pathogenic?

LIPA p.Ile252= (c.756A>C) is classified Benign/Likely benign in LIPA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Rare (popmax 0.548%, afr); Associated with Cardiovascular phenotype.

What condition is associated with LIPA p.Ile252= (c.756A>C)?

LIPA p.Ile252= (c.756A>C) is associated with Cardiovascular phenotype, Wolman disease, lysosomal acid lipase deficiency (ClinVar).

How common is LIPA p.Ile252= (c.756A>C) in the general population?

LIPA p.Ile252= (c.756A>C) is rare (popmax 0.548%, afr) (gnomAD).

LIPA p.Ile252=

c.756A>C · rs145037134 · VCV198408

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.548%, 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 0.25	GERP -3.9, phastCons 0.001
Overall
CADD	5.484	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.548% African / African-American · 411/75,038 alleles

Filtering AF 0.504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.487%

Overall 0.0291% 470/1,613,748 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.548%	183
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.0416%	2,401
South Asian	0.0022%	45,538
European (non-Finnish)	8.48e-05%	1,179,658

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.Ile252=
Coding: c.756A>C
MANE Select: NM_006552 · reported on NM_000235
dbSNP: rs145037134
Type: single nucleotide variant
Location: chr10:89223750 (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 lysosomal acid lipase deficiency

Similar variants

LIPA p.Ile252Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
LIPA p.Ile252Val 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-ile252 (accessed [today's date]).

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