# NM_003742.4(ABCB11):c.216T>C (p.His72=)

https://sugi.bio/variant/abcb11-p-his72

## Summary

**ABCB11 p.His72= (c.216T>C)** is classified **Conflicting classifications of pathogenicity** in ABCB11 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-14). Very rare (popmax 0.00934%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1174260635 · 2 submitters · very rare (popmax 0.00934%, 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 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 | [ABCB11](https://sugi.bio/atlas/gene/ABCB11/) |
| Protein change (HGVS p.) | p.His72= |
| Coding change (HGVS c.) | c.216T>C |
| MANE Select transcript | [NM_003742](https://www.ncbi.nlm.nih.gov/nuccore/NM_003742) |
| dbSNP | [rs1174260635](https://www.ncbi.nlm.nih.gov/snp/rs1174260635/) |
| Variant type | single nucleotide variant |
| Location | chr2:169013445-169013445 (GRCh38) |
| ClinVar | [VCV502691](https://www.ncbi.nlm.nih.gov/clinvar/variation/502691/) |

**All HGVS expressions:** `LRG_1199:g.22952T>C`, `LRG_1199t1:c.216T>C`, `NC_000002.11:g.169869955A>G`, `NC_000002.12:g.169013445A>G`, `NG_007374.2:g.22952T>C`, `NM_003742.4:c.216T>C`

## 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 2.343, GERP -0.475, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.801**. 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 (A>C, Δ0.36 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 **0.00934%** (afr) · FAF95 0.00437% · FAF99 0.00309% · 7/74,920 in the highest group · 8/1,613,686 alleles overall — very rare (popmax 0.00934%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00934% | 10,703 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,598 |

*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 **72** lies in the abc transmembrane type-1 1 domain; an α-helix.

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.His72= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-12-14.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2017–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-06-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-14 |

**Reported phenotype names (ClinVar):** not provided, 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+1G>A](/variant/abcb11-c-150-plus-1g-a), [ABCB11 c.150+2T>C](/variant/abcb11-c-150-plus-2t-c), [ABCB11 c.150+3A>C](/variant/abcb11-c-150-plus-3a-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 502691). 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.*