# NM_022436.3(ABCG5):c.1209C>T (p.Phe403=)

https://sugi.bio/variant/abcg5-p-phe403

## Summary

**ABCG5 p.Phe403= (c.1209C>T)** is classified **Likely benign** in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). Very rare (popmax 0.00667%, afr); Associated with sitosterolemia.

**At a glance:** Likely benign · review: Single submitter · rsID rs765896139 · 1 submitter · 1 linked condition · very rare (popmax 0.00667%, afr)

## 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.Phe403= |
| Coding change (HGVS c.) | c.1209C>T |
| MANE Select transcript | [NM_022436](https://www.ncbi.nlm.nih.gov/nuccore/NM_022436) |
| dbSNP | [rs765896139](https://www.ncbi.nlm.nih.gov/snp/rs765896139/) |
| Variant type | single nucleotide variant |
| Location | chr2:43824028-43824028 (GRCh38) |
| ClinVar | [VCV2139198](https://www.ncbi.nlm.nih.gov/clinvar/variation/2139198/) |

**All HGVS expressions:** `LRG_1181:g.19792C>T`, `LRG_1181t1:c.1209C>T`, `NC_000002.11:g.44051167G>A`, `NC_000002.12:g.43824028G>A`, `NG_008883.1:g.19792C>T`, `NG_053008.1:g.54990G>A`, `NM_001348912.2:c.*16-3358G>A`, `NM_001348913.2:c.*16-3358G>A`, `NM_022436.3:c.1209C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.33) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.513, GERP -0.005, phastCons 0.416 — weakly conserved position
- CADD: **PHRED 15.27**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.03**, acceptor gain **0.33**, donor gain **0.07**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.33**, donor gain **0.07**.
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (afr) · FAF95 0.00255% · FAF99 0.00161% · 5/74,922 in the highest group · 12/1,614,082 alleles overall — very rare (popmax 0.00667%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00667% | 14,984 |
| Admixed American | 0.00167% | 59,998 |
| European (non-Finnish) | 0.000508% | 196,675 |

*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 **403** lies in the abc transmembrane type-2 domain; an α-helix.

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.Phe403= falls in the abc transmembrane type-2 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 2025-09-02.

**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 | 2025-09-02 |

## 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 2139198). 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.*