# NM_002340.6(LSS):c.864G>C (p.Pro288=)

https://sugi.bio/variant/lss-p-pro288

## Summary

**LSS p.Pro288= (c.864G>C)** is classified **Benign** in LSS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with alopecia-intellectual disability syndrome 4.

**At a glance:** Benign · review: Multiple submitters · rsID rs9980968 · 4 submitters · 2 linked conditions · common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the LSS gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to alopecia-intellectual disability syndrome 4.

*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) | Neonatal |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | LSS is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Alopecia-intellectual disability syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Alopecia — Very frequent (99-80%)
- Sparse scalp hair — Very frequent (99-80%)
- Sparse body hair — Very frequent (99-80%)
- Delayed skeletal maturation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016386/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LSS](https://sugi.bio/atlas/gene/LSS/) |
| Protein change (HGVS p.) | p.Pro288= |
| Coding change (HGVS c.) | c.864G>C |
| MANE Select transcript | [NM_002340](https://www.ncbi.nlm.nih.gov/nuccore/NM_002340) |
| dbSNP | [rs9980968](https://www.ncbi.nlm.nih.gov/snp/rs9980968/) |
| Variant type | single nucleotide variant |
| Location | chr21:46215713-46215713 (GRCh38) |
| ClinVar | [VCV677174](https://www.ncbi.nlm.nih.gov/clinvar/variation/677174/) |

**All HGVS expressions:** `NC_000021.8:g.47635627C>G`, `NC_000021.9:g.46215713C>G`, `NG_011510.1:g.18112G>C`, `NM_001001438.3:c.864G>C`, `NM_001145436.2:c.831G>C`, `NM_001145437.2:c.624G>C`, `NM_002340.6:c.864G>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -13.591, GERP -3.26 — fast-evolving / accelerated position
- CADD: **PHRED 0.078**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for LSS (1,714 scored positions, the nearest 6 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **45.1%** (afr) · FAF95 44.7% · FAF99 44.5% · 33,708/74,796 in the highest group · 621,026/1,610,250 alleles overall — common (popmax 45.1%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 53.9% | 2 |
| African / African-American (grpmax) | 45.1% | 2 |
| South Asian | 43.8% | 2 |
| Middle Eastern | 41.6% | 2 |
| European (non-Finnish) | 39.5% | 3 |
| Remaining individuals (not grpmax-eligible) | 38.2% | 3 |
| Finnish (not grpmax-eligible) | 36.7% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 36.2% | 3 |
| Admixed American | 27.3% | 4 |
| East Asian | 12.8% | 8 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**LSS** population constraint: LOEUF 1.05, pLI 3.7781e-27, missense-Z 0.5765; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **288** lies in a UniProt-annotated variant site (in apmr4; loss of protein expression); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 98.05, 98% of residues very-high.

**2 experimental structure(s)** (PDB): [1W6J](https://www.rcsb.org/structure/1W6J), [1W6K](https://www.rcsb.org/structure/1W6K).

## What this gene does {#gene-function}

*Describes the biological roles of LSS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** LSS's established molecular role includes lanosterol synthase activity.


### Pathways affected {#pathways}

LSS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Lanosterol biosynthesis](https://reactome.org/content/detail/R-HSA-9969896) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** lanosterol synthase activity.

**Biological process:** steroid biosynthetic process, cholesterol biosynthetic process, regulation of protein stability.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (5/5 Benign).

**Submission history:** 5 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-03-24 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[alopecia-intellectual disability syndrome 4](https://sugi.bio/atlas/disease/alopecia-intellectual-disability-syndrome-4/), [cataract 44](https://sugi.bio/atlas/disease/cataract-44/).

**Reported phenotype names (ClinVar):** Alopecia-intellectual disability syndrome 4, not provided, Cataract 44, none provided, ALOPECIA-MENTAL RETARDATION SYNDROME 4, CATARACT 44 AND HYPOTRICHOSIS.

## Similar variants {#similar}

Related LSS variant pages (same residue, condition, or type): [LSS p.Arg177Gln](/variant/lss-p-arg177gln), [LSS p.Asn516Ser](/variant/lss-p-asn516ser), [LSS p.Trp216Ter](/variant/lss-p-trp216ter), [LSS p.Tyr286Cys](/variant/lss-p-tyr286cys), [LSS p.Gly522Arg](/variant/lss-p-gly522arg), [LSS c.551-6G>C](/variant/lss-c-551-minus-6g-c), [LSS c.784-6C>T](/variant/lss-c-784-minus-6c-t), [LSS p.Ala251Val](/variant/lss-p-ala251val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 677174). 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.*