# NM_001606.5(ABCA2):c.4542C>T (p.Arg1514=)

https://sugi.bio/variant/abca2-p-arg1514

## Summary

**ABCA2 p.Arg1514= (c.4542C>T)** is classified **Likely benign** in ABCA2 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-10-23). Rare (popmax 0.138%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs201649376 · 3 submitters · rare (popmax 0.138%, nfe)

## For patients & families {#patients}

This is a change in the ABCA2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [ABCA2](https://sugi.bio/atlas/gene/ABCA2/) |
| Protein change (HGVS p.) | p.Arg1514= |
| Coding change (HGVS c.) | c.4542C>T |
| MANE Select transcript | [NM_001606](https://www.ncbi.nlm.nih.gov/nuccore/NM_001606) |
| dbSNP | [rs201649376](https://www.ncbi.nlm.nih.gov/snp/rs201649376/) |
| Variant type | single nucleotide variant |
| Location | chr9:137013469-137013469 (GRCh38) |
| ClinVar | [VCV3044326](https://www.ncbi.nlm.nih.gov/clinvar/variation/3044326/) |

**All HGVS expressions:** `NC_000009.11:g.139907921G>A`, `NC_000009.12:g.137013469G>A`, `NG_011789.1:g.20454C>T`, `NM_001411042.1:c.4539C>T`, `NM_001606.5:c.4542C>T`, `NM_212533.3:c.4632C>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 **donor gain** (Δ 0.94) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.847, GERP -2.84 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 20.9**. 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 **0.01**, acceptor gain **0.00**, donor gain **0.94**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.94**.
- Pangolin: Δ**0.70** (gain), gain 0.70 / loss 0.22. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.138%** (nfe) · FAF95 0.132% · FAF99 0.13% · 1,625/1,177,806 in the highest group · 1,751/1,605,688 alleles overall — rare (popmax 0.138%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.138% | 725 |
| Remaining individuals (not grpmax-eligible) | 0.0948% | 1,055 |
| Finnish (not grpmax-eligible) | 0.0666% | 1,501 |
| African / African-American | 0.0173% | 5,767 |
| East Asian | 0.00897% | 11,152 |
| South Asian | 0.00894% | 11,180 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00342% | 29,252 |

*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}

**ABCA2** population constraint: LOEUF 0.436, pLI 0.99999, missense-Z 3.7441. *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 **1514** lies in a UniProt-annotated variant site (in idpogsa).

AlphaFold model confidence (whole protein): pLDDT 71.46, 10% of residues very-high.

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

*Describes the biological roles of ABCA2 (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:** ABCA2's established molecular role includes ATP binding.


### Pathways affected {#pathways}

ABCA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |

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

**Molecular function:** ATP binding, endopeptidase regulator activity, ceramide floppase activity.

**Biological process:** regulation of steroid metabolic process, regulation of intracellular cholesterol transport, negative regulation of intracellular cholesterol transport, positive regulation of low-density lipoprotein particle receptor catabolic process, cholesterol homeostasis, positive regulation of amyloid precursor protein biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-23.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-06-23 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-23 |

**Reported phenotype names (ClinVar):** ABCA2-related disorder, Cholangiocarcinoma, not specified, AllHighlyPenetrant, ABCA2-related condition.

## Similar variants {#similar}

Related ABCA2 variant pages (same residue, condition, or type): [ABCA2 p.Arg1514His](/variant/abca2-p-arg1514his), [ABCA2 p.Arg1514Ser](/variant/abca2-p-arg1514ser), [ABCA2 p.Gln1370Ter](/variant/abca2-p-gln1370ter), [ABCA2 c.3883-3C>T](/variant/abca2-c-3883-minus-3c-t), [ABCA2 p.Ala1357Thr](/variant/abca2-p-ala1357thr), [ABCA2 p.Ala1620Thr](/variant/abca2-p-ala1620thr), [ABCA2 p.Ala1645Val](/variant/abca2-p-ala1645val), [ABCA2 p.Ala1715Ser](/variant/abca2-p-ala1715ser).

### 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 3044326). 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.*