# NM_000235.4(LIPA):c.386A>C (p.His129Pro)

https://sugi.bio/variant/lipa-p-his129pro

## Summary

**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.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1423914418 · 2 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the LIPA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to cholesteryl ester storage disease.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Czech Republic) |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Lysosomal acid lipase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Jaundice — Very frequent (99-80%)
- Xanthomatosis — Very frequent (99-80%)
- Hepatic fibrosis — Very frequent (99-80%)
- Hepatic failure — Very frequent (99-80%)
- Decreased liver function — Very frequent (99-80%)
- Microvesicular hepatic steatosis — Very frequent (99-80%)
- Hepatosplenomegaly — Very frequent (99-80%)
- Vacuolated lymphocytes — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012099/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LIPA](https://sugi.bio/atlas/gene/LIPA/) |
| Protein change (HGVS p.) | p.His129Pro |
| Coding change (HGVS c.) | c.386A>C |
| MANE Select transcript | [NM_006552](https://www.ncbi.nlm.nih.gov/nuccore/NM_006552) (variant reported on NM_000235) |
| dbSNP | [rs1423914418](https://www.ncbi.nlm.nih.gov/snp/rs1423914418/) |
| Variant type | single nucleotide variant |
| Location | chr10:89228242-89228242 (GRCh38) |
| ClinVar | [VCV695056](https://www.ncbi.nlm.nih.gov/clinvar/variation/695056/) |

**All HGVS expressions:** `NC_000010.10:g.90987999T>G`, `NC_000010.11:g.89228242T>G`, `NG_008194.1:g.28662A>C`, `NM_000235.4:c.386A>C`, `NM_001127605.3:c.386A>C`, `NM_001288979.2:c.38A>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8668) — concordant with the pathogenic call
- REVEL 0.862 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.019 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.655, GERP 1.95, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in LIPA (of 515 modeled).
- CADD: **PHRED 27.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.94 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/1,461,880 alleles overall — very rare (popmax 8.47e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **lysosomal acid lipase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.74, 67% of residues very-high.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-23.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Alexion, Astrazeneca Rare Disease, Astrazeneca | Likely pathogenic | criteria provided, single submitter | research | 2019-06-01 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-23 |

## Associated conditions {#conditions}

[cholesteryl ester storage disease](https://sugi.bio/atlas/disease/cholesteryl-ester-storage-disease/), [Wolman disease](https://sugi.bio/atlas/disease/wolman-disease/), [lysosomal acid lipase deficiency](https://sugi.bio/atlas/disease/lysosomal-acid-lipase-deficiency/).

**Reported phenotype names (ClinVar):** Cholesteryl ester storage disease, Lysosomal acid lipase deficiency, Wolman disease, Childhood/Adult-Onset LAL-D (Cholesterol Ester Storage Disease [CESD]), Acid cholesteryl ester hydrolase deficiency, Wolman type, Acid lipase disease, Wolman disease, CESD, LYSOSOMAL ACID LIPASE DEFICIENCY, ACUTE INFANTILE, LYSOSOMAL ACID LIPASE DEFICIENCY, COMPLETE, LIPA DEFICIENCY, COMPLETE.

## Same-residue context {#hotspot}

Residue **129** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [LIPA p.His129Arg](/variant/lipa-p-his129arg). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LIPA variant pages (same residue, condition, or type): [LIPA p.His129Arg](/variant/lipa-p-his129arg), [LIPA c.111+1G>A](/variant/lipa-c-111-plus-1g-a), [LIPA c.539-2A>G](/variant/lipa-c-539-minus-2a-g), [LIPA c.675+2T>G](/variant/lipa-c-675-plus-2t-g), [LIPA c.676-2A>T](/variant/lipa-c-676-minus-2a-t), [LIPA c.822+1G>A](/variant/lipa-c-822-plus-1g-a), [LIPA c.823-2A>G](/variant/lipa-c-823-minus-2a-g), [LIPA c.894+1G>A](/variant/lipa-c-894-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 695056). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*