# NM_000443.4(ABCB4):c.1784G>A (p.Arg595Gln)

https://sugi.bio/variant/abcb4-p-arg595gln

## Summary

**ABCB4 p.Arg595Gln (c.1784G>A)** is classified **Uncertain significance** in ABCB4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0929); Ultra-rare (popmax 0.0534%, afr); Associated with cholestasis, intrahepatic, of pregnancy, 3.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs144398632 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0534%, afr)

## For patients & families {#patients}

This is a change in the ABCB4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, and is linked to cholestasis, intrahepatic, of pregnancy, 3.

*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) | Multigenic/multifactorial, Not applicable |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | ABCB4 is a diagnostic-grade gene on 8 Genomics England panels |

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

- Pruritus — Very frequent (99-80%)
- Increased serum bile acid concentration — Very frequent (99-80%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)
- Abnormality of the digestive system — Frequent (79-30%)
- Insomnia — Frequent (79-30%)
- Preeclampsia — Occasional (29-5%)
- Depression — Occasional (29-5%)
- Neonatal respiratory distress — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015888/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.Arg595Gln |
| Coding change (HGVS c.) | c.1784G>A |
| MANE Select transcript | [NM_000443](https://www.ncbi.nlm.nih.gov/nuccore/NM_000443) |
| dbSNP | [rs144398632](https://www.ncbi.nlm.nih.gov/snp/rs144398632/) |
| Variant type | single nucleotide variant |
| Location | chr7:87431513-87431513 (GRCh38) |
| ClinVar | [VCV360801](https://www.ncbi.nlm.nih.gov/clinvar/variation/360801/) |

**All HGVS expressions:** `NC_000007.13:g.87060829C>T`, `NC_000007.14:g.87431513C>T`, `NG_007118.2:g.53920G>A`, `NM_000443.4:c.1784G>A`, `NM_018849.3:c.1784G>A`, `NM_018850.3:c.1784G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0929)
- REVEL 0.386 (indeterminate)
- SaProt LLR -6.465 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 2.757, GERP 1.86, phastCons 0.994 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.0**. 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 0.97** across the covering region of the MANE Select transcript (87,417,392–87,431,529), spanning 14,137 bp. Chi-square p 0.53. 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 **0.0534%** (afr) · FAF95 0.0402% · FAF99 0.0357% · 40/74,916 in the highest group · 89/1,614,002 alleles overall — ultra-rare (popmax 0.0534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0534% | 1,873 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,414 |
| Finnish (not grpmax-eligible) | 0.00468% | 21,345 |
| European (non-Finnish) | 0.00322% | 31,053 |
| South Asian | 0.0022% | 45,541 |

*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 **595** lies in the abc transporter 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.Arg595Gln falls in the abc transporter 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-08.

**Submitter consensus:** unanimous (6/6 Uncertain significance).

**Submission history:** 6 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-05-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-08 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cholestasis, intrahepatic, of pregnancy, 3, Progressive familial intrahepatic cholestasis type 3, not provided, none provided, Low Gamma-GT Familial Intrahepatic Cholestasis, MDR3 DEFICIENCY.

## Same-residue context {#hotspot}

Residue **595** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCB4 p.Arg595Ter](/variant/abcb4-p-arg595ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCB4 variant pages (same residue, condition, or type): [ABCB4 p.Arg595Ter](/variant/abcb4-p-arg595ter), [ABCB4 p.Arg595Gly](/variant/abcb4-p-arg595gly), [ABCB4 c.1560+1G>A](/variant/abcb4-c-1560-plus-1g-a), [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.3081+1G>C](/variant/abcb4-c-3081-plus-1g-c), [ABCB4 c.3486+1G>A](/variant/abcb4-c-3486-plus-1g-a), [ABCB4 c.834-1G>A](/variant/abcb4-c-834-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 360801). 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.*