# NM_000392.5(ABCC2):c.2934G>A (p.Ser978=)

https://sugi.bio/variant/abcc2-p-ser978

## Summary

**ABCC2 p.Ser978= (c.2934G>A)** is classified **Benign** in ABCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Low-frequency (popmax 3.52%, eas); Associated with Dubin-Johnson syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs3740070 · 3 submitters · 1 linked condition · low-frequency (popmax 3.52%, eas)

## For patients & families {#patients}

This is a change in the ABCC2 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters, and is linked to Dubin-Johnson syndrome.

*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, Adult |
| Diagnostic panels | ABCC2 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Dubin-Johnson syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Jaundice — Very frequent (99-80%)
- Biliary tract abnormality — Very frequent (99-80%)
- Abnormality of the liver — Very frequent (99-80%)
- Conjugated hyperbilirubinemia — Very frequent (99-80%)
- Abnormal urinary color — Very frequent (99-80%)
- Abnormality of the gastric mucosa — Frequent (79-30%)
- Abnormality of coagulation — Occasional (29-5%)
- Fever — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002793/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCC2](https://sugi.bio/atlas/gene/ABCC2/) |
| Protein change (HGVS p.) | p.Ser978= |
| Coding change (HGVS c.) | c.2934G>A |
| MANE Select transcript | [NM_000392](https://www.ncbi.nlm.nih.gov/nuccore/NM_000392) |
| dbSNP | [rs3740070](https://www.ncbi.nlm.nih.gov/snp/rs3740070/) |
| Variant type | single nucleotide variant |
| Location | chr10:99831661-99831661 (GRCh38) |
| ClinVar | [VCV732860](https://www.ncbi.nlm.nih.gov/clinvar/variation/732860/) |

**All HGVS expressions:** `LRG_1208:g.54064G>A`, `LRG_1208t1:c.2934G>A`, `NC_000010.10:g.101591418G>A`, `NC_000010.11:g.99831661G>A`, `NG_011798.2:g.54064G>A`, `NM_000392.5:c.2934G>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 -9.002, GERP -4.96 — fast-evolving / accelerated position
- CADD: **PHRED 0.035**. 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: **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 **3.52%** (eas) · FAF95 3.37% · FAF99 3.31% · 1,578/44,878 in the highest group · 2,149/1,614,140 alleles overall — low-frequency (popmax 3.52%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 3.52% | 28 |
| Remaining individuals (not grpmax-eligible) | 0.133% | 753 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.111% | 897 |
| South Asian | 0.0648% | 1,544 |
| European (non-Finnish) | 0.0328% | 3,049 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.00667% | 15,004 |
| Admixed American | 0.005% | 20,003 |

*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}

**ABCC2** population constraint: LOEUF 0.985, pLI 1.5473e-45, missense-Z 1.0363. *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 **978** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.40, 38% of residues very-high.

**16 experimental structure(s)** (PDB): [8IZQ](https://www.rcsb.org/structure/8IZQ), [8IZR](https://www.rcsb.org/structure/8IZR), [8JX7](https://www.rcsb.org/structure/8JX7), [8JXQ](https://www.rcsb.org/structure/8JXQ), [8JXU](https://www.rcsb.org/structure/8JXU), [8JY4](https://www.rcsb.org/structure/8JY4).

## What this gene does {#gene-function}

*Describes the biological roles of ABCC2 (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:** ABCC2's established molecular role includes ABC-type xenobiotic transporter activity. In Reactome, ABCC2 is annotated in disease pathway(s) including **Defective ABCC2 causes DJS**.

**Disease mechanism (Reactome):** ABCC2 loss or alteration is curated in [Defective ABCC2 causes DJS](https://reactome.org/content/detail/R-HSA-5679001).

### Pathways affected {#pathways}

ABCC2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCC2 causes DJS](https://reactome.org/content/detail/R-HSA-5679001) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [Aspirin ADME](https://reactome.org/content/detail/R-HSA-9749641) | curated |
| [Atorvastatin ADME](https://reactome.org/content/detail/R-HSA-9754706) | curated |
| [Heme degradation](https://reactome.org/content/detail/R-HSA-189483) | curated |
| [Paracetamol ADME](https://reactome.org/content/detail/R-HSA-9753281) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ABC-type xenobiotic transporter activity, bilirubin transmembrane transporter activity, ABC-type glutathione S-conjugate transporter activity, ATPase-coupled transmembrane transporter activity, xenobiotic transmembrane transporter activity.

**Biological process:** xenobiotic transmembrane transport, bile acid and bile salt transport, bilirubin transport, heme catabolic process, xenobiotic export from cell, leukotriene transport.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[Dubin-Johnson syndrome](https://sugi.bio/atlas/disease/dubin-johnson-syndrome/).

**Reported phenotype names (ClinVar):** Dubin-Johnson syndrome, not provided, none provided, Hyperbilirubinemia type 2, Jaundice, Chronic Idiopathic, HYPERBILIRUBINEMIA, DUBIN-JOHNSON TYPE.

## Similar variants {#similar}

Related ABCC2 variant pages (same residue, condition, or type): [ABCC2 p.Ser978Leu](/variant/abcc2-p-ser978leu), [ABCC2 c.1031+4A>G](/variant/abcc2-c-1031-plus-4a-g), [ABCC2 c.3258+1G>A](/variant/abcc2-c-3258-plus-1g-a), [ABCC2 c.333+1G>A](/variant/abcc2-c-333-plus-1g-a), [ABCC2 c.3415-1G>A](/variant/abcc2-c-3415-minus-1g-a), [ABCC2 c.3741+1G>A](/variant/abcc2-c-3741-plus-1g-a), [ABCC2 c.3741+1G>T](/variant/abcc2-c-3741-plus-1g-t), [ABCC2 c.576+1G>A](/variant/abcc2-c-576-plus-1g-a).

### 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 732860). 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.*