# NM_000443.4(ABCB4):c.303G>A (p.Ser101=)

https://sugi.bio/variant/abcb4-p-ser101

## Summary

**ABCB4 p.Ser101= (c.303G>A)** is classified **Conflicting classifications of pathogenicity** in ABCB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-21). Very rare (popmax 0.00111%, sas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs886044650 · 3 submitters · very rare (popmax 0.00111%, sas)

## For patients & families {#patients}

This is a change in the ABCB4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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 | [ABCB4](https://sugi.bio/atlas/gene/ABCB4/) |
| Protein change (HGVS p.) | p.Ser101= |
| Coding change (HGVS c.) | c.303G>A |
| MANE Select transcript | [NM_000443](https://www.ncbi.nlm.nih.gov/nuccore/NM_000443) |
| dbSNP | [rs886044650](https://www.ncbi.nlm.nih.gov/snp/rs886044650/) |
| Variant type | single nucleotide variant |
| Location | chr7:87454576-87454576 (GRCh38) |
| ClinVar | [VCV291098](https://www.ncbi.nlm.nih.gov/clinvar/variation/291098/) |

**All HGVS expressions:** `NC_000007.13:g.87083892C>T`, `NC_000007.14:g.87454576C>T`, `NG_007118.2:g.30857G>A`, `NM_000443.3:c.303G>A`, `NM_000443.4:c.303G>A`, `NM_018849.3:c.303G>A`, `NM_018850.3:c.303G>A`

## 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 -0.227, GERP -3.73, phastCons 0.495 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.787**. 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, Δ0.48 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 **0.00111%** (sas) · 1/90,438 in the highest group · 2/1,458,480 alleles overall — very rare (popmax 0.00111%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00111% | 90,438 |
| European (non-Finnish) | 8.49e-05% | 1,177,838 |

*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 **101** lies in the abc transmembrane type-1 1 domain.

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. p.Ser101= falls in the abc transmembrane type-1 1 domain. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-21.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2017–2024); 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 | 2017-11-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-04-01 |

**Reported phenotype names (ClinVar):** not provided, ABCB4-related disorder, none provided, ABCB4-related disorders, ABCB4-related condition.

## Similar variants {#similar}

Related ABCB4 variant pages (same residue, condition, or type): [ABCB4 p.Ser101Leu](/variant/abcb4-p-ser101leu), [ABCB4 c.1006-2A>C](/variant/abcb4-c-1006-minus-2a-c), [ABCB4 c.1356+2T>C](/variant/abcb4-c-1356-plus-2t-c), [ABCB4 c.1560+1G>A](/variant/abcb4-c-1560-plus-1g-a), [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 291098). 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.*