# NM_004996.4(ABCC1):c.4296C>T (p.Val1432=)

https://sugi.bio/variant/abcc1-p-val1432

## Summary

**ABCC1 p.Val1432= (c.4296C>T)** is classified **Likely benign** in ABCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). Ultra-rare (popmax 0.0504%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs753509205 · 1 submitter · ultra-rare (popmax 0.0504%, mid)

## For patients & families {#patients}

This is a change in the ABCC1 gene that is classified as likely benign — not considered disease-causing, 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 | [ABCC1](https://sugi.bio/atlas/gene/ABCC1/) |
| Protein change (HGVS p.) | p.Val1432= |
| Coding change (HGVS c.) | c.4296C>T |
| MANE Select transcript | [NM_004996](https://www.ncbi.nlm.nih.gov/nuccore/NM_004996) |
| dbSNP | [rs753509205](https://www.ncbi.nlm.nih.gov/snp/rs753509205/) |
| Variant type | single nucleotide variant |
| Location | chr16:16138367-16138367 (GRCh38) |
| ClinVar | [VCV2646260](https://www.ncbi.nlm.nih.gov/clinvar/variation/2646260/) |

**All HGVS expressions:** `NC_000016.10:g.16138367C>T`, `NC_000016.9:g.16232224C>T`, `NG_028268.2:g.193791C>T`, `NM_004996.4:c.4296C>T`, `NM_019862.3:c.4119C>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 (below), not from a missing predictor score.
- Conservation: phyloP -20, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 0.052**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.97 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0504%** (mid) · FAF95 0.0136% · FAF99 0.00731% · 3/5,952 in the highest group · 97/1,580,104 alleles overall — ultra-rare (popmax 0.0504%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0504% | 1,984 |
| European (non-Finnish) | 0.00702% | 14,245 |
| Admixed American | 0.00682% | 14,655 |
| South Asian | 0.00559% | 17,882 |
| Remaining individuals (not grpmax-eligible) | 0.00494% | 20,263 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,550 |

*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}

**ABCC1** population constraint: LOEUF 0.564, pLI 1.2436e-06, missense-Z 2.0321. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autosomal dominant nonsyndromic hearing loss** — Limited (AD)

## Protein context {#protein}

Residue **1432** lies in the abc transporter 2 domain.

AlphaFold model confidence (whole protein): pLDDT 83.01, 42% of residues very-high.

**5 experimental structure(s)** (PDB): [2CBZ](https://www.rcsb.org/structure/2CBZ), [4C3Z](https://www.rcsb.org/structure/4C3Z), [8VT4](https://www.rcsb.org/structure/8VT4), [8VUX](https://www.rcsb.org/structure/8VUX), [8VVC](https://www.rcsb.org/structure/8VVC).

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

*Describes the biological roles of ABCC1 (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:** ABCC1's established molecular role includes ABC-type vitamin B12 transporter activity. p.Val1432= falls in the abc transporter 2 domain.


### Pathways affected {#pathways}

ABCC1 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Heme degradation](https://reactome.org/content/detail/R-HSA-189483) | curated |
| [NFE2L2 regulating MDR associated enzymes](https://reactome.org/content/detail/R-HSA-9818032) | curated |
| [Paracetamol ADME](https://reactome.org/content/detail/R-HSA-9753281) | curated |
| [Sphingolipid de novo biosynthesis](https://reactome.org/content/detail/R-HSA-1660661) | curated |
| [Synthesis of Leukotrienes (LT) and Eoxins (EX)](https://reactome.org/content/detail/R-HSA-2142691) | curated |
| [Transport of RCbl within the body](https://reactome.org/content/detail/R-HSA-9758890) | curated |

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

**Molecular function:** ABC-type vitamin B12 transporter activity, efflux transmembrane transporter activity, ATPase-coupled lipid transmembrane transporter activity, xenobiotic transmembrane transporter activity, carboxylic acid transmembrane transporter activity, ABC-type transporter activity.

**Biological process:** phospholipid translocation, transepithelial transport, cyclic nucleotide transport, sphingolipid translocation, export across plasma membrane, carboxylic acid transmembrane transport.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-01 |

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

## Similar variants {#similar}

Related ABCC1 variant pages (same residue, condition, or type): [ABCC1 p.Thr1464Met](/variant/abcc1-p-thr1464met), [ABCC1 c.1381-5C>G](/variant/abcc1-c-1381-minus-5c-g), [ABCC1 p.Ala1260=](/variant/abcc1-p-ala1260), [ABCC1 p.Ala1406=](/variant/abcc1-p-ala1406), [ABCC1 p.Arg433Ser](/variant/abcc1-p-arg433ser), [ABCC1 p.Asp637=](/variant/abcc1-p-asp637), [ABCC1 p.Gly762=](/variant/abcc1-p-gly762), [ABCC1 p.Gly885=](/variant/abcc1-p-gly885).

### 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 2646260). 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.*