# NM_005502.4(ABCA1):c.3159T>G (p.Val1053=)

https://sugi.bio/variant/abca1-p-val1053

## Summary

**ABCA1 p.Val1053= (c.3159T>G)** is classified **Benign/Likely benign** in ABCA1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.18%, nfe); Associated with Tangier disease.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs35871586 · 10 submitters · 2 linked conditions · low-frequency (popmax 1.18%, nfe)

## For patients & families {#patients}

This is a change in the ABCA1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to Tangier disease.

*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) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA1 is a diagnostic-grade gene on 8 Genomics England panels |

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

- Hypertriglyceridemia — Very frequent (99-80%)
- Hypocholesterolemia — Very frequent (99-80%)
- Ectropion — Frequent (79-30%)
- Dry skin — Frequent (79-30%)
- Hepatosplenomegaly — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Distal muscle weakness — Frequent (79-30%)
- Chronic noninfectious lymphadenopathy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007731/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCA1](https://sugi.bio/atlas/gene/ABCA1/) |
| Protein change (HGVS p.) | p.Val1053= |
| Coding change (HGVS c.) | c.3159T>G |
| MANE Select transcript | [NM_005502](https://www.ncbi.nlm.nih.gov/nuccore/NM_005502) |
| dbSNP | [rs35871586](https://www.ncbi.nlm.nih.gov/snp/rs35871586/) |
| Variant type | single nucleotide variant |
| Location | chr9:104819668-104819668 (GRCh38) |
| ClinVar | [VCV364421](https://www.ncbi.nlm.nih.gov/clinvar/variation/364421/) |

**All HGVS expressions:** `LRG_542:g.113488T>G`, `LRG_542t1:c.3159T>G`, `NC_000009.11:g.107581949A>C`, `NC_000009.12:g.104819668A>C`, `NG_007981.1:g.113488T>G`, `NM_005502.4:c.3159T>G`

## 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 -0.064, GERP -3.1, phastCons 0.013 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.586**. 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 (gnomAD v4.1): grpmax **1.18%** (nfe) · FAF95 1.17% · FAF99 1.16% · 13,973/1,180,034 in the highest group · 16,131/1,614,208 alleles overall — low-frequency (popmax 1.18%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 1.18% | 84 |
| Finnish (not grpmax-eligible) | 1.14% | 88 |
| Remaining individuals (not grpmax-eligible) | 0.918% | 109 |
| Admixed American | 0.453% | 221 |
| South Asian | 0.423% | 237 |
| African / African-American | 0.179% | 560 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.172% | 581 |
| Amish (not grpmax-eligible) | 0.11% | 912 |
| Middle Eastern | 0.099% | 1,010 |
| East Asian | 0.00891% | 11,220 |

*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}

**ABCA1** population constraint: LOEUF 0.563, pLI 2.3118e-12, missense-Z 3.076. *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 **1053** lies in the abc transporter 1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 73.50, 6% of residues very-high.

**7 experimental structure(s)** (PDB): [5XJY](https://www.rcsb.org/structure/5XJY), [7ROQ](https://www.rcsb.org/structure/7ROQ), [7TBW](https://www.rcsb.org/structure/7TBW), [7TBY](https://www.rcsb.org/structure/7TBY), [7TBZ](https://www.rcsb.org/structure/7TBZ), [7TC0](https://www.rcsb.org/structure/7TC0).

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

*Describes the biological roles of ABCA1 (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:** ABCA1's established molecular role includes signaling receptor binding. p.Val1053= falls in the abc transporter 1 domain. In Reactome, ABCA1 is annotated in disease pathway(s) including **Defective ABCA1 causes TGD**.

**Disease mechanism (Reactome):** ABCA1 loss or alteration is curated in [Defective ABCA1 causes TGD](https://reactome.org/content/detail/R-HSA-5682113).

### Pathways affected {#pathways}

ABCA1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCA1 causes TGD](https://reactome.org/content/detail/R-HSA-5682113) | curated |
| [HDL assembly](https://reactome.org/content/detail/R-HSA-8963896) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

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

**Molecular function:** signaling receptor binding, ATP binding, obsolete phospholipid transporter activity, syntaxin binding, phosphatidylcholine binding, small GTPase binding.

**Biological process:** lysosome organization, G protein-coupled receptor signaling pathway, adenylate cyclase-activating G protein-coupled receptor signaling pathway, cholesterol metabolic process, protein secretion, endosomal transport.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (7 Benign, 3 Likely benign).

**Submission history:** 19 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-10 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-07-15 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2016-05-30 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2019-09-10 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

## Associated conditions {#conditions}

[Tangier disease](https://sugi.bio/atlas/disease/tangier-disease/), [hypoalphalipoproteinemia, primary, 1](https://sugi.bio/atlas/disease/hypoalphalipoproteinemia-primary-1/).

**Reported phenotype names (ClinVar):** Tangier disease, Hypoalphalipoproteinemia, primary, 1, not provided, Cardiovascular phenotype, Acute myeloid leukemia, Nonpapillary renal cell carcinoma, Thyroid cancer, nonmedullary, 1, Hepatocellular carcinoma, Lung cancer, Cervical cancer.

## Similar variants {#similar}

Related ABCA1 variant pages (same residue, condition, or type): [ABCA1 c.5237+3A>C](/variant/abca1-c-5237-plus-3a-c), [ABCA1 p.Arg2080Trp](/variant/abca1-p-arg2080trp), [ABCA1 p.Arg587Trp](/variant/abca1-p-arg587trp), [ABCA1 p.Asn1800His](/variant/abca1-p-asn1800his), [ABCA1 c.*2330A>T](/variant/abca1-c-star-2330a-t), [ABCA1 c.*379C>T](/variant/abca1-c-star-379c-t), [ABCA1 p.Arg126Cys](/variant/abca1-p-arg126cys), [ABCA1 p.Arg1342Trp](/variant/abca1-p-arg1342trp).

### 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 364421). 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.*