# NM_000392.5(ABCC2):c.3500dup (p.Ser1168fs)

https://sugi.bio/variant/abcc2-p-ser1168fs

## Summary

**ABCC2 p.Ser1168fs (c.3500dup)** is classified **Pathogenic** in ABCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-04). Very rare (popmax 0.00167%, amr).

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1333544687 · 2 submitters · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ABCC2 gene that is considered disease-causing, 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 | [ABCC2](https://sugi.bio/atlas/gene/ABCC2/) |
| Protein change (HGVS p.) | p.Ser1168fs |
| Coding change (HGVS c.) | c.3500dup |
| MANE Select transcript | [NM_000392](https://www.ncbi.nlm.nih.gov/nuccore/NM_000392) |
| dbSNP | [rs1333544687](https://www.ncbi.nlm.nih.gov/snp/rs1333544687/) |
| Variant type | Duplication |
| Location | chr10:99836175-99836176 (GRCh38) |
| ClinVar | [VCV498805](https://www.ncbi.nlm.nih.gov/clinvar/variation/498805/) |

**All HGVS expressions:** `LRG_1208:g.58579dup`, `LRG_1208t1:c.3500dup`, `NC_000010.10:g.101595933dup`, `NC_000010.11:g.99836176dup`, `NG_011798.2:g.58579dup`, `NM_000392.5:c.3500dup`

## Computational & population evidence {#evidence}

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

- **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 8.552, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.985, pLI 1.5473e-45. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 25 of 32**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000359% · FAF99 0.00026% · 1/60,002 in the highest group · 13/1,614,058 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,239 |
| Admixed American (grpmax) | 0.00167% | 60,002 |
| African / African-American | 0.00133% | 74,928 |
| European (non-Finnish) | 0.000763% | 131,116 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **1168** lies in an α-helix; the abc transmembrane type-1 2 domain.

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. p.Ser1168fs falls in the abc transmembrane type-1 2 domain. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-04.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2016–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2016-11-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ABCC2 variant pages (same residue, condition, or type): [ABCC2 p.Asp1073Ter](/variant/abcc2-p-asp1073ter), [ABCC2 p.Leu1213fs](/variant/abcc2-p-leu1213fs), [ABCC2 p.Lys298fs](/variant/abcc2-p-lys298fs), [ABCC2 p.Val667fs](/variant/abcc2-p-val667fs), [ABCC2 p.Ala579fs](/variant/abcc2-p-ala579fs), [ABCC2 p.Asp210Ter](/variant/abcc2-p-asp210ter), [ABCC2 p.Asp304fs](/variant/abcc2-p-asp304fs), [ABCC2 p.Gly853fs](/variant/abcc2-p-gly853fs).

### 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 498805). 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.*