# NM_000392.5(ABCC2):c.516C>T (p.Tyr172=)

https://sugi.bio/variant/abcc2-p-tyr172

## Summary

**ABCC2 p.Tyr172= (c.516C>T)** is classified **Likely benign** in ABCC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-22). Ultra-rare (popmax 0.0117%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs766116167 · 2 submitters · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the ABCC2 gene that is classified as likely benign — not 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.Tyr172= |
| Coding change (HGVS c.) | c.516C>T |
| MANE Select transcript | [NM_000392](https://www.ncbi.nlm.nih.gov/nuccore/NM_000392) |
| dbSNP | [rs766116167](https://www.ncbi.nlm.nih.gov/snp/rs766116167/) |
| Variant type | single nucleotide variant |
| Location | chr10:99793939-99793939 (GRCh38) |
| ClinVar | [VCV2428308](https://www.ncbi.nlm.nih.gov/clinvar/variation/2428308/) |

**All HGVS expressions:** `LRG_1208:g.16342C>T`, `LRG_1208t1:c.516C>T`, `NC_000010.10:g.101553696C>T`, `NC_000010.11:g.99793939C>T`, `NG_011798.2:g.16342C>T`, `NM_000392.4:c.516C>T`, `NM_000392.5:c.516C>T`

## 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 -1.374, GERP -5.15, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.607**. 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>G, Δ0.54 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 **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.00381% · 7/59,990 in the highest group · 24/1,613,762 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0117% | 8,570 |
| East Asian | 0.00446% | 22,446 |
| African / African-American | 0.00267% | 37,456 |
| South Asian | 0.0022% | 45,543 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,480 |
| European (non-Finnish) | 0.000848% | 117,988 |

*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 **172** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-22.

**Submitter consensus:** unanimous (2/2 Likely benign).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-03-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-22 |

**Reported phenotype names (ClinVar):** not provided, ABCC2-related disorder, ABCC2-related condition, none provided.

## Same-residue context {#hotspot}

Residue **172** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCC2 p.Tyr172fs](/variant/abcc2-p-tyr172fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCC2 variant pages (same residue, condition, or type): [ABCC2 p.Tyr172fs](/variant/abcc2-p-tyr172fs), [ABCC2 c.1031+4A>G](/variant/abcc2-c-1031-plus-4a-g), [ABCC2 c.1967+1G>A](/variant/abcc2-c-1967-plus-1g-a), [ABCC2 c.1968-1G>C](/variant/abcc2-c-1968-minus-1g-c), [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.3414+1G>A](/variant/abcc2-c-3414-plus-1g-a), [ABCC2 c.3415-1G>A](/variant/abcc2-c-3415-minus-1g-a).

### 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 2428308). 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.*