# NM_003742.4(ABCB11):c.1281C>T (p.Phe427=)

https://sugi.bio/variant/abcb11-p-phe427

## Summary

**ABCB11 p.Phe427= (c.1281C>T)** is classified **Conflicting classifications of pathogenicity** in ABCB11 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-14). Rare (popmax 0.323%, afr); Associated with familial intrahepatic cholestasis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs11568360 · 6 submitters · 2 linked conditions · rare (popmax 0.323%, afr)

## For patients & families {#patients}

This is a change in the ABCB11 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to familial intrahepatic cholestasis.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0021119/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCB11](https://sugi.bio/atlas/gene/ABCB11/) |
| Protein change (HGVS p.) | p.Phe427= |
| Coding change (HGVS c.) | c.1281C>T |
| MANE Select transcript | [NM_003742](https://www.ncbi.nlm.nih.gov/nuccore/NM_003742) |
| dbSNP | [rs11568360](https://www.ncbi.nlm.nih.gov/snp/rs11568360/) |
| Variant type | single nucleotide variant |
| Location | chr2:168976604-168976604 (GRCh38) |
| ClinVar | [VCV284547](https://www.ncbi.nlm.nih.gov/clinvar/variation/284547/) |

**All HGVS expressions:** `LRG_1199:g.59793C>T`, `LRG_1199t1:c.1281C>T`, `NC_000002.11:g.169833114G>A`, `NC_000002.12:g.168976604G>A`, `NG_007374.2:g.59793C>T`, `NM_003742.4:c.1281C>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 3.792, GERP 0.224, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.69**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.323%** (afr) · FAF95 0.29% · FAF99 0.277% · 242/74,812 in the highest group · 344/1,605,956 alleles overall — rare (popmax 0.323%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.323% | 309 |
| Middle Eastern | 0.166% | 603 |
| Remaining individuals (not grpmax-eligible) | 0.045% | 2,221 |
| Admixed American | 0.0201% | 4,975 |
| European (non-Finnish) | 0.00435% | 23,015 |
| South Asian | 0.0011% | 90,514 |

*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}

**ABCB11** population constraint: LOEUF 0.739, pLI 9.5597e-15, missense-Z 1.2052; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}

Residue **427** lies in a β-strand; the abc transporter 1 domain.

AlphaFold model confidence (whole protein): pLDDT 83.23, 51% of residues very-high.

**9 experimental structure(s)** (PDB): [36CG](https://www.rcsb.org/structure/36CG), [7DV5](https://www.rcsb.org/structure/7DV5), [7E1A](https://www.rcsb.org/structure/7E1A), [8PM6](https://www.rcsb.org/structure/8PM6), [6LR0](https://www.rcsb.org/structure/6LR0), [8PMD](https://www.rcsb.org/structure/8PMD).

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

*Describes the biological roles of ABCB11 (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:** ABCB11's established molecular role includes ABC-type xenobiotic transporter activity. p.Phe427= falls in the abc transporter 1 domain. In Reactome, ABCB11 is annotated in disease pathway(s) including **Defective ABCB11 causes PFIC2 and BRIC2**.

**Disease mechanism (Reactome):** ABCB11 loss or alteration is curated in [Defective ABCB11 causes PFIC2 and BRIC2](https://reactome.org/content/detail/R-HSA-5678520).

### Pathways affected {#pathways}

ABCB11 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCB11 causes PFIC2 and BRIC2](https://reactome.org/content/detail/R-HSA-5678520) | curated |
| [Recycling of bile acids and salts](https://reactome.org/content/detail/R-HSA-159418) | curated |
| [Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol](https://reactome.org/content/detail/R-HSA-193368) | curated |

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

**Molecular function:** ABC-type xenobiotic transporter activity, bile acid transmembrane transporter activity, canalicular bile acid transmembrane transporter activity, ABC-type bile acid transporter activity.

**Biological process:** xenobiotic metabolic process, xenobiotic transmembrane transport, bile acid metabolic process, bile acid and bile salt transport, canalicular bile acid transport, protein ubiquitination.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-14.

**Submitter consensus:** conflicting (4 Likely benign, 2 Uncertain significance).

**Submission history:** 6 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-11-30 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-08 |
| Genomenon, Inc, Genomenon, Inc | Likely benign | criteria provided, single submitter | curation | 2026-04-14 |

## Associated conditions {#conditions}

[familial intrahepatic cholestasis](https://sugi.bio/atlas/disease/familial-intrahepatic-cholestasis/), [progressive familial intrahepatic cholestasis type 2](https://sugi.bio/atlas/disease/progressive-familial-intrahepatic-cholestasis-type-2/).

**Reported phenotype names (ClinVar):** Familial intrahepatic cholestasis, not specified, not provided, Progressive familial intrahepatic cholestasis type 2, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related ABCB11 variant pages (same residue, condition, or type): [ABCB11 c.1084-2A>G](/variant/abcb11-c-1084-minus-2a-g), [ABCB11 c.1197+1G>T](/variant/abcb11-c-1197-plus-1g-t), [ABCB11 c.1198-1G>C](/variant/abcb11-c-1198-minus-1g-c), [ABCB11 c.1198-2A>C](/variant/abcb11-c-1198-minus-2a-c), [ABCB11 c.1435-2A>T](/variant/abcb11-c-1435-minus-2a-t), [ABCB11 c.150+2T>C](/variant/abcb11-c-150-plus-2t-c), [ABCB11 c.150+3A>C](/variant/abcb11-c-150-plus-3a-c), [ABCB11 c.1638+1G>C](/variant/abcb11-c-1638-plus-1g-c).

### 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 284547). 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.*