# NM_172232.4(ABCA5):c.4521G>A (p.Val1507=)

https://sugi.bio/variant/abca5-p-val1507

## Summary

**ABCA5 p.Val1507= (c.4521G>A)** is classified **Likely benign** in ABCA5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-25). Ultra-rare (popmax 0.0936%, eas); Associated with ABCA5-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs199848425 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0936%, eas)

## For patients & families {#patients}

This is a change in the ABCA5 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to ABCA5-related disorder.

*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 | [ABCA5](https://sugi.bio/atlas/gene/ABCA5/) |
| Protein change (HGVS p.) | p.Val1507= |
| Coding change (HGVS c.) | c.4521G>A |
| MANE Select transcript | [NM_172232](https://www.ncbi.nlm.nih.gov/nuccore/NM_172232) |
| dbSNP | [rs199848425](https://www.ncbi.nlm.nih.gov/snp/rs199848425/) |
| Variant type | single nucleotide variant |
| Location | chr17:69251761-69251761 (GRCh38) |
| ClinVar | [VCV3042879](https://www.ncbi.nlm.nih.gov/clinvar/variation/3042879/) |

**All HGVS expressions:** `NC_000017.10:g.67247902C>T`, `NC_000017.11:g.69251761C>T`, `NG_034199.1:g.80422G>A`, `NM_018672.5:c.4521G>A`, `NM_172232.4:c.4521G>A`

## 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 0.77) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.381, GERP -2.37 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.14**. 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 **0.18**, acceptor gain **0.00**, donor gain **0.77**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.77**.
- Pangolin: Δ**0.60** (gain), gain 0.60 / loss 0.17. 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 **0.0936%** (eas) · FAF95 0.0712% · FAF99 0.0632% · 42/44,862 in the highest group · 53/1,613,940 alleles overall — ultra-rare (popmax 0.0936%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0936% | 1,068 |
| African / African-American | 0.00666% | 15,007 |
| Admixed American | 0.00334% | 29,981 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| European (non-Finnish) | 0.000169% | 589,981 |

*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}

**ABCA5** population constraint: LOEUF 0.97, pLI 1.7677e-24, missense-Z 0.33724. *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 **1507** lies in the abc transporter 2 domain.

AlphaFold model confidence (whole protein): pLDDT 77.12, 12% of residues very-high.

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

*Describes the biological roles of ABCA5 (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.*


### Pathways affected {#pathways}

ABCA5 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}

**Biological process:** cholesterol metabolic process, regulation of cholesterol efflux, cholesterol homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-06-25.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-25 |

## Associated conditions {#conditions}

[ABCA5-related disorder](https://sugi.bio/atlas/disease/abca5-related-disorder/).

**Reported phenotype names (ClinVar):** ABCA5-related disorder, ABCA5-related condition.

## Similar variants {#similar}

Related ABCA5 variant pages (same residue, condition, or type): [ABCA5 c.4415+3G>A](/variant/abca5-c-4415-plus-3g-a), [ABCA5 c.788+8A>C](/variant/abca5-c-788-plus-8a-c), [ABCA5 p.Ala1444=](/variant/abca5-p-ala1444), [ABCA5 p.Ala178Thr](/variant/abca5-p-ala178thr), [ABCA5 p.Arg555=](/variant/abca5-p-arg555), [ABCA5 p.Gln484Arg](/variant/abca5-p-gln484arg), [ABCA5 p.Leu1131=](/variant/abca5-p-leu1131), [ABCA5 p.Leu1183=](/variant/abca5-p-leu1183).

### 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 3042879). 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.*