# NM_022436.3(ABCG5):c.1619C>T (p.Ala540Val)

https://sugi.bio/variant/abcg5-p-ala540val

## Summary

**ABCG5 p.Ala540Val (c.1619C>T)** is classified **Uncertain significance** in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely benign (0.1626); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ABCG5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [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.Ala540Val |
| Coding change (HGVS c.) | c.1619C>T |
| MANE Select transcript | [NM_022436](https://www.ncbi.nlm.nih.gov/nuccore/NM_022436) |
| Variant type | single nucleotide variant |
| Location | chr2:43819945-43819945 (GRCh38) |
| ClinVar | [VCV3311782](https://www.ncbi.nlm.nih.gov/clinvar/variation/3311782/) |

**All HGVS expressions:** `LRG_1181:g.23875C>T`, `LRG_1181t1:c.1619C>T`, `NC_000002.11:g.44047084G>A`, `NC_000002.12:g.43819945G>A`, `NG_008883.1:g.23875C>T`, `NG_053008.1:g.50907G>A`, `NM_001348912.2:c.*16-7441G>A`, `NM_001348913.2:c.*16-7441G>A`, `NM_022436.3:c.1619C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1626)
- REVEL 0.313 (indeterminate)
- SaProt LLR -5.035 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 6.554, GERP 0.84, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.3**. 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.*
- Regional missense constraint: **o/e 1.09** across the covering region of the MANE Select transcript (43,813,119–43,838,679), spanning 25,560 bp. Chi-square p 0.0064. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.24 donor loss), 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 **0.0011%** (sas) · FAF95 0.000542% · FAF99 0.000428% · 1/91,070 in the highest group · 15/1,461,868 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| South Asian (grpmax) | 0.0011% | 91,070 |
| European (non-Finnish) | 0.00102% | 98,330 |

Remaining individuals 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}

**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 **540** 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.Ala540Val 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-20 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related ABCG5 variant pages (same residue, condition, or type): [ABCG5 p.Ala540=](/variant/abcg5-p-ala540), [ABCG5 c.1325-1G>T](/variant/abcg5-c-1325-minus-1g-t), [ABCG5 p.Gln251Ter](/variant/abcg5-p-gln251ter), [ABCG5 p.Glu146Ter](/variant/abcg5-p-glu146ter), [ABCG5 p.Ala170Asp](/variant/abcg5-p-ala170asp), [ABCG5 p.Ala264Val](/variant/abcg5-p-ala264val), [ABCG5 p.Ala278Glu](/variant/abcg5-p-ala278glu), [ABCG5 p.Ala333Ser](/variant/abcg5-p-ala333ser).

### 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 3311782). 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.*