# NM_003742.4(ABCB11):c.896_897delinsTT (p.Arg299Ile)

https://sugi.bio/variant/abcb11-p-arg299ile

## Summary

**ABCB11 p.Arg299Ile (c.896_897delinsTT)** is classified **Uncertain significance** in ABCB11 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-14). No gnomAD frequency available for this variant; Associated with progressive familial intrahepatic cholestasis type 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2106004734 · 5 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ABCB11 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, and is linked to progressive familial intrahepatic cholestasis type 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Childhood, Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCB11 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Progressive familial intrahepatic cholestasis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Jaundice — Very frequent (99-80%)
- Cholestasis — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Splenomegaly — Very frequent (99-80%)
- Abnormality of coagulation — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001288/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.Arg299Ile |
| Coding change (HGVS c.) | c.896_897delinsTT |
| MANE Select transcript | [NM_003742](https://www.ncbi.nlm.nih.gov/nuccore/NM_003742) |
| dbSNP | [rs2106004734](https://www.ncbi.nlm.nih.gov/snp/rs2106004734/) |
| Variant type | Indel |
| Location | chr2:168990812-168990813 (GRCh38) |
| ClinVar | [VCV1310347](https://www.ncbi.nlm.nih.gov/clinvar/variation/1310347/) |

**All HGVS expressions:** `LRG_1199:g.45584_45585delinsTT`, `LRG_1199t1:c.896_897delinsTT`, `NC_000002.11:g.169847322_169847323delinsAA`, `NC_000002.12:g.168990812_168990813delinsAA`, `NG_007374.2:g.45584_45585delinsTT`, `NM_003742.4:c.896_897delinsTT`

## 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 2.851, GERP -1.66, phastCons 0.999 — highly conserved position (PP3-type support)
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **299** lies in an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (in).

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.Arg299Ile falls in the abc transmembrane type-1 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}

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

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-22 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-02-06 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2026-04-14 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Clinical Genomics Laboratory, Washington University in St. Louis | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Progressive familial intrahepatic cholestasis type 2, not provided, ABCB11-related disorder, Familial intrahepatic cholestasis, ABCB11-related condition, none provided.

## Similar variants {#similar}

Related ABCB11 variant pages (same residue, condition, or type): [ABCB11 p.Arg299Lys](/variant/abcb11-p-arg299lys), [ABCB11 p.Lys1043fs](/variant/abcb11-p-lys1043fs), [ABCB11 c.2177_2178+1delinsGT](/variant/abcb11-c-2177-2178-plus-1delinsgt), [ABCB11 c.3213+1_3213+2delinsA](/variant/abcb11-c-3213-plus-1-3213-plus-2delinsa), [ABCB11 p.Leu241fs](/variant/abcb11-p-leu241fs), [ABCB11 p.Ser1154fs](/variant/abcb11-p-ser1154fs), [ABCB11 p.Thr1121fs](/variant/abcb11-p-thr1121fs), [ABCB11 p.Arg299Ser](/variant/abcb11-p-arg299ser).

### 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 1310347). 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.*