# NM_022437.3(ABCG8):c.1596C>T (p.Phe532=)

https://sugi.bio/variant/abcg8-p-phe532

## Summary

**ABCG8 p.Phe532= (c.1596C>T)** is classified **Conflicting classifications of pathogenicity** in ABCG8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-15). Very rare (popmax 0.00667%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs374820261 · 5 submitters · 1 linked condition · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the ABCG8 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, 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 | [ABCG8](https://sugi.bio/atlas/gene/ABCG8/) |
| Protein change (HGVS p.) | p.Phe532= |
| Coding change (HGVS c.) | c.1596C>T |
| MANE Select transcript | [NM_022437](https://www.ncbi.nlm.nih.gov/nuccore/NM_022437) |
| dbSNP | [rs374820261](https://www.ncbi.nlm.nih.gov/snp/rs374820261/) |
| Variant type | single nucleotide variant |
| Location | chr2:43875253-43875253 (GRCh38) |
| ClinVar | [VCV593989](https://www.ncbi.nlm.nih.gov/clinvar/variation/593989/) |

**All HGVS expressions:** `LRG_1182:g.48312C>T`, `LRG_1182t1:c.1596C>T`, `NC_000002.11:g.44102392C>T`, `NC_000002.12:g.43875253C>T`, `NG_008884.2:g.48312C>T`, `NM_001357321.2:c.1593C>T`, `NM_022437.3:c.1596C>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 (below), not from a missing predictor score.
- Conservation: phyloP 1.081, GERP -1.6, phastCons 0.546 — weakly conserved position
- CADD: **PHRED 8.602**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.33 acceptor gain), 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 **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00198% · 4/60,014 in the highest group · 41/1,614,124 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 15,004 |
| European (non-Finnish) | 0.00305% | 32,779 |
| African / African-American | 0.00133% | 74,952 |

*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}

**ABCG8** population constraint: LOEUF 1.329, pLI 5.1931e-31, missense-Z -2.6097; 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 **532** lies in the abc transmembrane type-2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.94, 39% 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 ABCG8 (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:** ABCG8's established molecular role includes ATPase-coupled transmembrane transporter activity. p.Phe532= falls in the abc transmembrane type-2 domain. In Reactome, ABCG8 is annotated in disease pathway(s) including **Defective ABCG5 causes sitosterolemia**, **Defective ABCG8 causes GBD4 and sitosterolemia**.

**Disease mechanism (Reactome):** ABCG8 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}

ABCG8 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-03-15.

**Submitter consensus:** conflicting (4 Likely benign, 1 Uncertain significance).

**Submission history:** 5 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-09-06 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-26 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-11-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-15 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, ABCG8-related disorder, not specified, AllHighlyPenetrant, none provided, ABCG8-related condition.

## Similar variants {#similar}

Related ABCG8 variant pages (same residue, condition, or type): [ABCG8 p.Phe532Tyr](/variant/abcg8-p-phe532tyr), [ABCG8 p.Arg121Ter](/variant/abcg8-p-arg121ter), [ABCG8 p.Arg405Cys](/variant/abcg8-p-arg405cys), [ABCG8 p.Gln271Ter](/variant/abcg8-p-gln271ter), [ABCG8 p.Ala248Thr](/variant/abcg8-p-ala248thr), [ABCG8 p.Ala346Thr](/variant/abcg8-p-ala346thr), [ABCG8 p.Ala449Val](/variant/abcg8-p-ala449val), [ABCG8 p.Ala450Thr](/variant/abcg8-p-ala450thr).

### 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 593989). 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.*