# NM_022436.3(ABCG5):c.651T>C (p.Asp217=)

https://sugi.bio/variant/abcg5-p-asp217

## Summary

**ABCG5 p.Asp217= (c.651T>C)** is classified **Likely benign** in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-27). Absent from gnomAD v4.1; Associated with sitosterolemia.

**At a glance:** Likely benign · review: Single submitter · rsID rs2466035530 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCG5 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to sitosterolemia.

*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) | All ages |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCG5 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Xanthomatosis — Frequent (79-30%)
- Splenomegaly — Frequent (79-30%)
- Hemolytic anemia — Frequent (79-30%)
- Giant platelets — Frequent (79-30%)
- Arthralgia — Frequent (79-30%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)
- Hypercholesterolemia — Frequent (79-30%)
- Stomatocytosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007653/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCG5](https://sugi.bio/atlas/gene/ABCG5/) |
| Protein change (HGVS p.) | p.Asp217= |
| Coding change (HGVS c.) | c.651T>C |
| MANE Select transcript | [NM_022436](https://www.ncbi.nlm.nih.gov/nuccore/NM_022436) |
| dbSNP | [rs2466035530](https://www.ncbi.nlm.nih.gov/snp/rs2466035530/) |
| Variant type | single nucleotide variant |
| Location | chr2:43826505-43826505 (GRCh38) |
| ClinVar | [VCV2839438](https://www.ncbi.nlm.nih.gov/clinvar/variation/2839438/) |

**All HGVS expressions:** `LRG_1181:g.17315T>C`, `LRG_1181t1:c.651T>C`, `NC_000002.11:g.44053644A>G`, `NC_000002.12:g.43826505A>G`, `NG_008883.1:g.17315T>C`, `NG_053008.1:g.57467A>G`, `NM_001348912.2:c.*16-881A>G`, `NM_001348913.2:c.*16-881A>G`, `NM_022436.3:c.651T>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 0.03, GERP -3.89, phastCons 0.063 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.023**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ABCG5** population constraint: LOEUF 1.219, pLI 8.1322e-20, missense-Z -1.0834; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **sitosterolemia** — Definitive (AR)

## Protein context {#protein}

Residue **217** lies in the abc transporter domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 85.48, 58% of residues very-high.

**8 experimental structure(s)** (PDB): [5DO7](https://www.rcsb.org/structure/5DO7), [7JR7](https://www.rcsb.org/structure/7JR7), [7R87](https://www.rcsb.org/structure/7R87), [7R88](https://www.rcsb.org/structure/7R88), [7R89](https://www.rcsb.org/structure/7R89), [7R8A](https://www.rcsb.org/structure/7R8A).

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

*Describes the biological roles of ABCG5 (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:** ABCG5's established molecular role includes ATPase-coupled transmembrane transporter activity. p.Asp217= falls in the abc transporter domain. In Reactome, ABCG5 is annotated in disease pathway(s) including **Defective ABCG5 causes sitosterolemia**, **Defective ABCG8 causes GBD4 and sitosterolemia**.

**Disease mechanism (Reactome):** ABCG5 loss or alteration is curated in [Defective ABCG5 causes sitosterolemia](https://reactome.org/content/detail/R-HSA-5679096), [Defective ABCG8 causes GBD4 and sitosterolemia](https://reactome.org/content/detail/R-HSA-5679090).

### Pathways affected {#pathways}

ABCG5 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCG5 causes sitosterolemia](https://reactome.org/content/detail/R-HSA-5679096) | curated |
| ⚕ [Defective ABCG8 causes GBD4 and sitosterolemia](https://reactome.org/content/detail/R-HSA-5679090) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |

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

**Molecular function:** ATPase-coupled transmembrane transporter activity, protein heterodimerization activity.

**Biological process:** negative regulation of intestinal phytosterol absorption, cholesterol efflux, cholesterol homeostasis, negative regulation of intestinal cholesterol absorption.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-27.

**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 | 2023-09-27 |

## Associated conditions {#conditions}

[sitosterolemia](https://sugi.bio/atlas/disease/sitosterolemia/).

**Reported phenotype names (ClinVar):** Sitosterolemia, PHYTOSTEROLEMIA.

## Similar variants {#similar}

Related ABCG5 variant pages (same residue, condition, or type): [ABCG5 c.1762+1G>A](/variant/abcg5-c-1762-plus-1g-a), [ABCG5 c.634+1G>C](/variant/abcg5-c-634-plus-1g-c), [ABCG5 c.904+1G>A](/variant/abcg5-c-904-plus-1g-a), [ABCG5 p.Arg183Ter](/variant/abcg5-p-arg183ter), [ABCG5 p.Arg243Ter](/variant/abcg5-p-arg243ter), [ABCG5 p.Arg389His](/variant/abcg5-p-arg389his), [ABCG5 p.Arg408Ter](/variant/abcg5-p-arg408ter), [ABCG5 p.Arg419His](/variant/abcg5-p-arg419his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2839438). 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.*