# NM_173076.3(ABCA12):c.69G>A (p.Pro23=)

https://sugi.bio/variant/abca12-p-pro23

## Summary

**ABCA12 p.Pro23= (c.69G>A)** is classified **Uncertain significance** in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2105925883 · 2 submitters · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ABCA12 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [ABCA12](https://sugi.bio/atlas/gene/ABCA12/) |
| Protein change (HGVS p.) | p.Pro23= |
| Coding change (HGVS c.) | c.69G>A |
| MANE Select transcript | [NM_173076](https://www.ncbi.nlm.nih.gov/nuccore/NM_173076) |
| dbSNP | [rs2105925883](https://www.ncbi.nlm.nih.gov/snp/rs2105925883/) |
| Variant type | single nucleotide variant |
| Location | chr2:215138140-215138140 (GRCh38) |
| ClinVar | [VCV1310229](https://www.ncbi.nlm.nih.gov/clinvar/variation/1310229/) |

**All HGVS expressions:** `NC_000002.11:g.216002863C>T`, `NC_000002.12:g.215138140C>T`, `NG_007074.1:g.5289G>A`, `NM_173076.3:c.69G>A`, `NR_103740.2:n.487G>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 loss** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.671, GERP 2.26, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 23.0**. 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 **0.48**, acceptor gain **0.00**, donor gain **0.08**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.08**.
  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.*
- Pangolin: Δ**0.43** (loss), gain 0.01 / loss 0.43. 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 **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/91,074 in the highest group · 3/1,461,762 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,074 |
| European (non-Finnish) | 0.00017% | 589,950 |

*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}

**ABCA12** population constraint: LOEUF 0.582, pLI 4.8142e-17, missense-Z 2.9254. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.32, 4% of residues very-high.

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

*Describes the biological roles of ABCA12 (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:** ABCA12's established molecular role includes signaling receptor binding. In Reactome, ABCA12 is annotated in disease pathway(s) including **Defective ABCA12 causes ARCI4B**.

**Disease mechanism (Reactome):** ABCA12 loss or alteration is curated in [Defective ABCA12 causes ARCI4B](https://reactome.org/content/detail/R-HSA-5682294).

### Pathways affected {#pathways}

ABCA12 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCA12 causes ARCI4B](https://reactome.org/content/detail/R-HSA-5682294) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |

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

**Molecular function:** signaling receptor binding, lipid carrier activity, apolipoprotein A-I receptor binding.

**Biological process:** corneocyte desquamation, ceramide metabolic process, lipid transport, intracellular protein transport, positive regulation of cholesterol efflux, secretion by cell.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ABCA12 variant pages (same residue, condition, or type): [ABCA12 c.2592+1G>A](/variant/abca12-c-2592-plus-1g-a), [ABCA12 c.5381+1G>C](/variant/abca12-c-5381-plus-1g-c), [ABCA12 c.985+1G>A](/variant/abca12-c-985-plus-1g-a), [ABCA12 p.Arg1297Ter](/variant/abca12-p-arg1297ter), [ABCA12 p.Arg1514Cys](/variant/abca12-p-arg1514cys), [ABCA12 p.Arg1514His](/variant/abca12-p-arg1514his), [ABCA12 p.Arg1515Ter](/variant/abca12-p-arg1515ter), [ABCA12 p.Arg1950Ter](/variant/abca12-p-arg1950ter).

### 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 1310229). 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.*