# NM_004827.3(ABCG2):c.369C>T (p.Tyr123=)

https://sugi.bio/variant/abcg2-p-tyr123

## Summary

**ABCG2 p.Tyr123= (c.369C>T)** is classified **Benign** in ABCG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-17). Common (popmax 6.78%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs2231139 · 2 submitters · common (popmax 6.78%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ABCG2 gene that is classified as 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 | [ABCG2](https://sugi.bio/atlas/gene/ABCG2/) |
| Protein change (HGVS p.) | p.Tyr123= |
| Coding change (HGVS c.) | c.369C>T |
| MANE Select transcript | [NM_004827](https://www.ncbi.nlm.nih.gov/nuccore/NM_004827) |
| dbSNP | [rs2231139](https://www.ncbi.nlm.nih.gov/snp/rs2231139/) |
| Variant type | single nucleotide variant |
| Location | chr4:88131812-88131812 (GRCh38) |
| ClinVar | [VCV787808](https://www.ncbi.nlm.nih.gov/clinvar/variation/787808/) |

**All HGVS expressions:** `LRG_823:g.104511C>T`, `LRG_823t1:c.369C>T`, `NC_000004.11:g.89052964G>A`, `NC_000004.12:g.88131812G>A`, `NG_032067.2:g.104511C>T`, `NM_001257386.2:c.369C>T`, `NM_001348985.1:c.369C>T`, `NM_001348986.2:c.369C>T`, `NM_001348987.1:c.369C>T`, `NM_001348988.1:c.369C>T`, `NM_001348989.2:c.369C>T`, `NM_004827.3:c.369C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.78%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -0.285, GERP -2.39, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.821**. 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 (G>C, Δ0.42 donor 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 **6.78%** (afr) · FAF95 6.62% · FAF99 6.56% · 5,080/74,962 in the highest group · 5,675/1,612,572 alleles overall — common (popmax 6.78%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 6.78% | 15 |
| Remaining individuals (not grpmax-eligible) | 0.413% | 242 |
| Admixed American | 0.398% | 251 |
| Middle Eastern | 0.237% | 423 |
| East Asian | 0.0134% | 7,476 |
| South Asian | 0.00989% | 10,109 |
| European (non-Finnish) | 0.00568% | 17,603 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,320 |

*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}

**ABCG2** population constraint: LOEUF 1.308, pLI 5.0723e-29, missense-Z 0.50878. *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 **123** lies in the abc transporter domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 85.54, 66% of residues very-high.

**29 experimental structure(s)** (PDB): [5NJ3](https://www.rcsb.org/structure/5NJ3), [5NJG](https://www.rcsb.org/structure/5NJG), [6ETI](https://www.rcsb.org/structure/6ETI), [6FEQ](https://www.rcsb.org/structure/6FEQ), [6FFC](https://www.rcsb.org/structure/6FFC), [6HBU](https://www.rcsb.org/structure/6HBU) — incl. mutant structure 6HBU.

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

*Describes the biological roles of ABCG2 (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:** ABCG2's established molecular role includes ABC-type xenobiotic transporter activity. p.Tyr123= falls in the abc transporter domain.


### Pathways affected {#pathways}

ABCG2 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ciprofloxacin ADME](https://reactome.org/content/detail/R-HSA-9793528) | curated |
| [Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin](https://reactome.org/content/detail/R-HSA-9725554) | curated |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |
| [Heme degradation](https://reactome.org/content/detail/R-HSA-189483) | curated |
| [Iron uptake and transport](https://reactome.org/content/detail/R-HSA-917937) | curated |
| [NFE2L2 regulating MDR associated enzymes](https://reactome.org/content/detail/R-HSA-9818032) | curated |
| [Paracetamol ADME](https://reactome.org/content/detail/R-HSA-9753281) | curated |
| [Sphingolipid de novo biosynthesis](https://reactome.org/content/detail/R-HSA-1660661) | curated |
| [Abacavir transmembrane transport](https://reactome.org/content/detail/R-HSA-2161517) | electronic |

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

**Molecular function:** ABC-type xenobiotic transporter activity, urate transmembrane transporter activity, efflux transmembrane transporter activity, riboflavin transmembrane transporter activity, ATPase-coupled transmembrane transporter activity, identical protein binding.

**Biological process:** riboflavin transport, urate metabolic process, transmembrane transport, transepithelial transport, renal urate salt excretion, cellular detoxification.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-08-17.

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

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-08-17 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

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

## Similar variants {#similar}

Related ABCG2 variant pages (same residue, condition, or type): [ABCG2 p.Ala505Gly](/variant/abcg2-p-ala505gly), [ABCG2 p.Arg575Gln](/variant/abcg2-p-arg575gln), [ABCG2 p.Asn289Lys](/variant/abcg2-p-asn289lys), [ABCG2 p.Asp312Gly](/variant/abcg2-p-asp312gly), [ABCG2 p.Asp419Tyr](/variant/abcg2-p-asp419tyr), [ABCG2 p.Gln324His](/variant/abcg2-p-gln324his), [ABCG2 p.Gln393Arg](/variant/abcg2-p-gln393arg), [ABCG2 p.Gln437Arg](/variant/abcg2-p-gln437arg).

### 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 787808). 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.*