Is LIPA p.His129Pro (c.386A>C) pathogenic?

LIPA p.His129Pro (c.386A>C) is classified Pathogenic/Likely pathogenic in LIPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-23). AlphaMissense: likely pathogenic (0.8668); Very rare (popmax 8.47e-05%, nfe); Associated with cholesteryl ester storage disease.

What condition is associated with LIPA p.His129Pro (c.386A>C)?

LIPA p.His129Pro (c.386A>C) is associated with cholesteryl ester storage disease, Wolman disease, lysosomal acid lipase deficiency (ClinVar).

How common is LIPA p.His129Pro (c.386A>C) in the general population?

LIPA p.His129Pro (c.386A>C) is very rare (popmax 8.47e-05%, nfe) (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.His129Pro (c.386A>C)?

AlphaMissense predicts likely pathogenic (score 0.8668) — an in-silico prediction, not a clinical call.

LIPA p.His129Pro

c.386A>C · rs1423914418 · VCV695056

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cholesteryl ester storage disease

Computational evidence

Protein change
AlphaMissense	0.8668	likely pathogenic ✓ concordant with ClinVar · top 1% in LIPA
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Overall
CADD	27.1	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.84e-05% 1/1,461,880 alleles · very rare

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.His129Pro
Coding: c.386A>C
MANE Select: NM_006552 · reported on NM_000235
dbSNP: rs1423914418
Type: single nucleotide variant
Location: chr10:89228242 (GRCh38)
Structure: AlphaFold pLDDT 89.74

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

Disease context

cholesteryl ester storage disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Wolman disease lysosomal acid lipase deficiency

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.His129Arg Pathogenic/Likely pathogenic ★★ 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
LIPA c.894+1G>A 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-his129pro (accessed [today's date]).

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