Is LIPA p.Asp376= (c.1128C>T) pathogenic?

LIPA p.Asp376= (c.1128C>T) is classified Conflicting classifications of pathogenicity in LIPA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.0134%, eas); Associated with Cardiovascular phenotype.

What condition is associated with LIPA p.Asp376= (c.1128C>T)?

LIPA p.Asp376= (c.1128C>T) is associated with Cardiovascular phenotype, Wolman disease, lysosomal acid lipase deficiency (ClinVar).

How common is LIPA p.Asp376= (c.1128C>T) in the general population?

LIPA p.Asp376= (c.1128C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

LIPA p.Asp376=

c.1128C>T · rs200420117 · VCV282717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

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 3.6	GERP 0.17, phastCons 1
Overall
CADD	8.222	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,878 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000434% 7/1,614,076 alleles · ultra-rare exomes 3/1,461,766 · genomes 4/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,480
South Asian	0.0011%	91,086

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.Asp376=
Coding: c.1128C>T
MANE Select: NM_000235
dbSNP: rs200420117
Type: single nucleotide variant
Location: chr10:89214900 (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 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
LIPA c.894+1G>A Pathogenic ★★ same condition
LIPA p.Ala307Asp 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-asp376 (accessed [today's date]).

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