# NM_000443.4(ABCB4):c.139C>T (p.Arg47Ter)

https://sugi.bio/variant/abcb4-p-arg47ter

## Summary

**ABCB4 p.Arg47Ter (c.139C>T)** is classified **Pathogenic** in ABCB4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-14). Very rare (popmax 0.00223%, eas); Associated with ABCB4-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs376926391 · 6 submitters · 3 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ABCB4 gene that is considered disease-causing, submitted by 6 submitters, and is linked to ABCB4-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 | [ABCB4](https://sugi.bio/atlas/gene/ABCB4/) |
| Protein change (HGVS p.) | p.Arg47Ter |
| Coding change (HGVS c.) | c.139C>T |
| MANE Select transcript | [NM_000443](https://www.ncbi.nlm.nih.gov/nuccore/NM_000443) |
| dbSNP | [rs376926391](https://www.ncbi.nlm.nih.gov/snp/rs376926391/) |
| Variant type | single nucleotide variant |
| Location | chr7:87462905-87462905 (GRCh38) |
| ClinVar | [VCV502776](https://www.ncbi.nlm.nih.gov/clinvar/variation/502776/) |

**All HGVS expressions:** `NC_000007.13:g.87092221G>A`, `NC_000007.14:g.87462905G>A`, `NG_007118.2:g.22528C>T`, `NM_000443.3:c.139C>T`, `NM_000443.4:c.139C>T`, `NM_018849.3:c.139C>T`, `NM_018850.3:c.139C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.948, GERP 1.02, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 28**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 39.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.62 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 **0.00223%** (eas) · FAF95 0.000365% · FAF99 0.00026% · 1/44,852 in the highest group · 14/1,612,712 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,852 |
| South Asian | 0.0022% | 45,486 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,442 |
| African / African-American | 0.00134% | 74,732 |
| European (non-Finnish) | 0.000763% | 131,035 |

*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}

**ABCB4** population constraint: LOEUF 0.623, pLI 1.7893e-08, missense-Z 3.5556; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **progressive familial intrahepatic cholestasis type 3** — Definitive (AR)

## Protein context {#protein}

Residue **47** lies in a turn; a UniProt-annotated variant site (in gbd1; partly retained intracellularly; reduces efflux activity for pc in a phosphorylation-dependent manner); a UniProt-annotated variant site (found in patients with cholangitis; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 83.36, 48% of residues very-high.

**4 experimental structure(s)** (PDB): [6S7P](https://www.rcsb.org/structure/6S7P), [7NIU](https://www.rcsb.org/structure/7NIU), [7NIV](https://www.rcsb.org/structure/7NIV), [7NIW](https://www.rcsb.org/structure/7NIW).

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

*Describes the biological roles of ABCB4 (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:** ABCB4's established molecular role includes ATPase-coupled transmembrane transporter activity. In Reactome, ABCB4 is annotated in disease pathway(s) including **Defective ABCB4 causes PFIC3, ICP3 and GBD1**.

**Disease mechanism (Reactome):** ABCB4 loss or alteration is curated in [Defective ABCB4 causes PFIC3, ICP3 and GBD1](https://reactome.org/content/detail/R-HSA-5678771).

### Pathways affected {#pathways}

ABCB4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCB4 causes PFIC3, ICP3 and GBD1](https://reactome.org/content/detail/R-HSA-5678771) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

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

**Molecular function:** ATPase-coupled transmembrane transporter activity, phosphatidylcholine floppase activity.

**Biological process:** positive regulation of cholesterol transport, phospholipid translocation, lipid homeostasis, positive regulation of phospholipid translocation, cellular response to bile acid, positive regulation of phospholipid transport.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-14.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-10 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-06-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-10 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2023-12-19 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2026-04-14 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-28 |

## Associated conditions {#conditions}

[ABCB4-related disorder](https://sugi.bio/atlas/disease/abcb4-related-disorder/), [gallbladder disease 1](https://sugi.bio/atlas/disease/gallbladder-disease-1/), [familial intrahepatic cholestasis](https://sugi.bio/atlas/disease/familial-intrahepatic-cholestasis/).

**Reported phenotype names (ClinVar):** ABCB4-related disorder, not provided, Familial intrahepatic cholestasis, Low phospholipid associated cholelithiasis, ABCB4-related disorders, ABCB4-related condition, none provided, Gallbladder disease 1, Gallstone cholecystitis.

## Same-residue context {#hotspot}

Residue **47** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCB4 p.Arg47Gly](/variant/abcb4-p-arg47gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCB4 variant pages (same residue, condition, or type): [ABCB4 p.Arg47Gly](/variant/abcb4-p-arg47gly), [ABCB4 p.Arg47Gln](/variant/abcb4-p-arg47gln), [ABCB4 p.Arg47=](/variant/abcb4-p-arg47), [ABCB4 c.1356+2T>C](/variant/abcb4-c-1356-plus-2t-c), [ABCB4 c.2064+3A>T](/variant/abcb4-c-2064-plus-3a-t), [ABCB4 c.2211+1G>A](/variant/abcb4-c-2211-plus-1g-a), [ABCB4 c.2682+1G>A](/variant/abcb4-c-2682-plus-1g-a), [ABCB4 c.2783+1G>T](/variant/abcb4-c-2783-plus-1g-t).

### 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 502776). 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.*