# NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)

https://sugi.bio/variant/abcb4-p-ser320phe

## Summary

**ABCB4 p.Ser320Phe (c.959C>T)** is classified **Pathogenic/Likely pathogenic** in ABCB4 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-09-01). AlphaMissense: likely pathogenic (0.6872); Ultra-rare (popmax 0.022%, nfe); Associated with familial intrahepatic cholestasis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs72552778 · 20 submitters · 5 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.022%, nfe)

## For patients & families {#patients}

This is a change in the ABCB4 gene that is considered likely disease-causing, submitted by 20 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 | [ABCB4](https://sugi.bio/atlas/gene/ABCB4/) |
| Protein change (HGVS p.) | p.Ser320Phe |
| Coding change (HGVS c.) | c.959C>T |
| MANE Select transcript | [NM_000443](https://www.ncbi.nlm.nih.gov/nuccore/NM_000443) |
| dbSNP | [rs72552778](https://www.ncbi.nlm.nih.gov/snp/rs72552778/) |
| Variant type | single nucleotide variant |
| Location | chr7:87447080-87447080 (GRCh38) |
| ClinVar | [VCV13690](https://www.ncbi.nlm.nih.gov/clinvar/variation/13690/) |

**All HGVS expressions:** `NC_000007.13:g.87076396G>A`, `NC_000007.14:g.87447080G>A`, `NG_007118.2:g.38353C>T`, `NM_000443.4:c.959C>T`, `NM_018849.3:c.959C>T`, `NM_018850.3:c.959C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6872) — concordant with the pathogenic call
- REVEL 0.835 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.466 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.747, GERP 1.86, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.4**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (87,431,530–87,462,832), spanning 31,302 bp. Chi-square p 4.4e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.022%** (nfe) · FAF95 0.0197% · FAF99 0.0189% · 259/1,179,716 in the highest group · 280/1,613,618 alleles overall — ultra-rare (popmax 0.022%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.022% | 4,555 |
| Admixed American | 0.0133% | 7,499 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,809 |
| South Asian | 0.00329% | 30,357 |
| African / African-American | 0.00267% | 37,453 |

*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 3/3, triplosensitivity 0/3. *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 **320** lies in an α-helix; the abc transmembrane type-1 1 domain; a UniProt-annotated variant site (in icp3, gbd1 and pfic3; uncertain significance; does not alter plasma membrane location; does not inhibit efflux activity for pc).

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.Ser320Phe 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-09-01.

**Submitter consensus:** conflicting (17 Pathogenic, 3 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 21 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | flagged submission | clinical testing | 2014-08-22 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-03-05 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-24 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-10-01 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Pathogenic | no assertion criteria provided | clinical testing |  |
| NIHR Bioresource Rare Diseases, University of Cambridge | Pathogenic | no assertion criteria provided | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-24 |
| Genomenon, Inc, Genomenon, Inc | Pathogenic | criteria provided, single submitter | curation | 2026-04-14 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-02 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-22 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | research | 2023-01-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-03 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-25 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-13 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-09-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-06 |

## Associated conditions {#conditions}

[familial intrahepatic cholestasis](https://sugi.bio/atlas/disease/familial-intrahepatic-cholestasis/), [gallbladder disease 1](https://sugi.bio/atlas/disease/gallbladder-disease-1/), [progressive familial intrahepatic cholestasis type 3](https://sugi.bio/atlas/disease/progressive-familial-intrahepatic-cholestasis-type-3/), [cholestasis, intrahepatic, of pregnancy, 3](https://sugi.bio/atlas/disease/cholestasis-intrahepatic-of-pregnancy-3/), [progressive familial intrahepatic cholestasis](https://sugi.bio/atlas/disease/progressive-familial-intrahepatic-cholestasis/).

**Reported phenotype names (ClinVar):** Familial intrahepatic cholestasis, Low phospholipid associated cholelithiasis, Cholestasis, intrahepatic, of pregnancy, 3, Progressive familial intrahepatic cholestasis type 3, not provided, Progressive familial intrahepatic cholestasis, ABCB4-related disorder, Autosomal recessive ABCB4-related disorders, Gallstone cholecystitis, Gallbladder disease 1.

## Similar variants {#similar}

Related ABCB4 variant pages (same residue, condition, or type): [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), [ABCB4 c.286+1G>A](/variant/abcb4-c-286-plus-1g-a), [ABCB4 c.3081+1G>C](/variant/abcb4-c-3081-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 13690). 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.*