# NM_000235.4(LIPA):c.276T>C (p.Ser92=)

https://sugi.bio/variant/lipa-p-ser92

## Summary

**LIPA p.Ser92= (c.276T>C)** is classified **Likely benign** in LIPA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-25). Very rare (popmax 8.47e-05%, nfe); Associated with Wolman disease.

**At a glance:** Likely benign · review: Single submitter · rsID rs2133436705 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the LIPA gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Wolman 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 | 30 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/0007899/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.Ser92= |
| Coding change (HGVS c.) | c.276T>C |
| MANE Select transcript | [NM_000235](https://www.ncbi.nlm.nih.gov/nuccore/NM_000235) |
| dbSNP | [rs2133436705](https://www.ncbi.nlm.nih.gov/snp/rs2133436705/) |
| Variant type | single nucleotide variant |
| Location | chr10:89228352-89228352 (GRCh38) |
| ClinVar | [VCV1537332](https://www.ncbi.nlm.nih.gov/clinvar/variation/1537332/) |

**All HGVS expressions:** `NC_000010.10:g.90988109A>G`, `NC_000010.11:g.89228352A>G`, `NG_008194.1:g.28552T>C`, `NM_000235.4:c.276T>C`, `NM_001127605.3:c.276T>C`, `NM_001288979.2:c.-73T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -4.553, GERP -3.9 — fast-evolving / accelerated position
- CADD: **PHRED 3.547**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/1,614,244 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-02-25.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-02-25 |

## Associated conditions {#conditions}

[Wolman disease](https://sugi.bio/atlas/disease/wolman-disease/).

**Reported phenotype names (ClinVar):** Wolman disease, LYSOSOMAL ACID LIPASE DEFICIENCY, ACUTE INFANTILE, LYSOSOMAL ACID LIPASE DEFICIENCY, COMPLETE, LIPA DEFICIENCY, COMPLETE, LAL DEFICIENCY, COMPLETE, CHOLESTEROL ESTER HYDROLASE DEFICIENCY, COMPLETE, Acid cholesteryl ester hydrolase deficiency, Wolman type, Acid lipase disease, Infantile-Onset LAL-D (Wolman Disease), Wolman disease with hypolipoproteinemia and acanthocytosis.

## Similar variants {#similar}

Related LIPA variant pages (same residue, condition, or type): [LIPA p.Ser92Tyr](/variant/lipa-p-ser92tyr), [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 2026-10-14); 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 1537332). 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.*