Is LIPA p.Val353Phe (c.1057G>T) pathogenic?

LIPA p.Val353Phe (c.1057G>T) is classified Uncertain significance in LIPA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). AlphaMissense: ambiguous (0.5241); Absent from gnomAD v4.1; Associated with Wolman disease.

What condition is associated with LIPA p.Val353Phe (c.1057G>T)?

LIPA p.Val353Phe (c.1057G>T) is associated with Wolman disease (ClinVar).

How common is LIPA p.Val353Phe (c.1057G>T) in the general population?

LIPA p.Val353Phe (c.1057G>T) is absent from gnomAD v4.1 (gnomAD).

How is Lysosomal acid lipase deficiency inherited?

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

What do computational predictors say about LIPA p.Val353Phe (c.1057G>T)?

AlphaMissense predicts ambiguous (score 0.5241) — an in-silico prediction, not a clinical call.

LIPA p.Val353Phe

c.1057G>T · VCV4709860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5241 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Wolman disease

Computational evidence

Protein change
AlphaMissense	0.5241	ambiguous · top 10% in LIPA
REVEL	0.32	indeterminate
SaProt	LLR -14.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.9
Overall
CADD	0.833	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LIPA
Protein: p.Val353Phe
Coding: c.1057G>T
MANE Select: NM_006552 · reported on NM_000235
Type: single nucleotide variant
Location: chr10:89214971 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Disease context

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

For Lysosomal acid lipase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Czech Republic)

Similar variants

LIPA p.Val353= Likely benign ★ same residue
LIPA p.Val353Ile Likely benign ★ 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-val353phe (accessed [today's date]).

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