# NM_172232.4(ABCA5):c.2045G>A (p.Arg682Lys)

https://sugi.bio/variant/abca5-p-arg682lys

## Summary

**ABCA5 p.Arg682Lys (c.2045G>A)** is classified **Uncertain significance** in ABCA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.5762); Ultra-rare (popmax 0.0369%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs372894277 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0369%, afr)

## For patients & families {#patients}

This is a change in the ABCA5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.Arg682Lys |
| Coding change (HGVS c.) | c.2045G>A |
| MANE Select transcript | [NM_172232](https://www.ncbi.nlm.nih.gov/nuccore/NM_172232) |
| dbSNP | [rs372894277](https://www.ncbi.nlm.nih.gov/snp/rs372894277/) |
| Variant type | single nucleotide variant |
| Location | chr17:69286308-69286308 (GRCh38) |
| ClinVar | [VCV3104230](https://www.ncbi.nlm.nih.gov/clinvar/variation/3104230/) |

**All HGVS expressions:** `NC_000017.10:g.67282449C>T`, `NC_000017.11:g.69286308C>T`, `NG_034199.1:g.45875G>A`, `NM_018672.5:c.2045G>A`, `NM_172232.4:c.2045G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.5762)
- REVEL 0.684 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.893 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor loss** (Δ 0.59) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.658, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.7**. 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 0.97** across the covering region of the MANE Select transcript (69,247,540–69,314,415), spanning 66,875 bp. Chi-square p 0.22. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.59**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0369%** (afr) · FAF95 0.026% · FAF99 0.0224% · 27/73,096 in the highest group · 29/1,589,652 alleles overall — ultra-rare (popmax 0.0369%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0369% | 2,707 |
| Admixed American | 0.0039% | 25,669 |

*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 **682** lies in the abc transporter 1 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-01.

**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 | 2024-03-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ABCA5 variant pages (same residue, condition, or type): [ABCA5 p.Ser288Phe](/variant/abca5-p-ser288phe), [ABCA5 c.4765+3A>G](/variant/abca5-c-4765-plus-3a-g), [ABCA5 p.Asn190Ser](/variant/abca5-p-asn190ser), [ABCA5 p.Asn768Asp](/variant/abca5-p-asn768asp), [ABCA5 p.Asp817Tyr](/variant/abca5-p-asp817tyr), [ABCA5 p.Gly1159Arg](/variant/abca5-p-gly1159arg), [ABCA5 p.Gly128=](/variant/abca5-p-gly128), [ABCA5 p.Ile1173Val](/variant/abca5-p-ile1173val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3104230). 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.*