# NM_003786.4(ABCC3):c.435G>A (p.Val145=)

https://sugi.bio/variant/abcc3-p-val145

## Summary

**ABCC3 p.Val145= (c.435G>A)** is classified **Benign** in ABCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-10). Rare (popmax 0.285%, sas).

**At a glance:** Benign · review: Single submitter · rsID rs538270581 · 1 submitter · rare (popmax 0.285%, sas)

## For patients & families {#patients}

This is a change in the ABCC3 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter.

*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 | [ABCC3](https://sugi.bio/atlas/gene/ABCC3/) |
| Protein change (HGVS p.) | p.Val145= |
| Coding change (HGVS c.) | c.435G>A |
| MANE Select transcript | [NM_003786](https://www.ncbi.nlm.nih.gov/nuccore/NM_003786) |
| dbSNP | [rs538270581](https://www.ncbi.nlm.nih.gov/snp/rs538270581/) |
| Variant type | single nucleotide variant |
| Location | chr17:50657132-50657132 (GRCh38) |
| ClinVar | [VCV739697](https://www.ncbi.nlm.nih.gov/clinvar/variation/739697/) |

**All HGVS expressions:** `NC_000017.10:g.48734493G>A`, `NC_000017.11:g.50657132G>A`, `NM_001144070.2:c.435G>A`, `NM_003786.4:c.435G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.592, GERP -2.12, phastCons 0.063 — weakly conserved position
- CADD: **PHRED 16.27**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.285%** (sas) · FAF95 0.257% · FAF99 0.246% · 260/91,082 in the highest group · 274/1,614,184 alleles overall — rare (popmax 0.285%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.285% | 350 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,251 |
| Admixed American | 0.00333% | 30,008 |
| African / African-American | 0.00133% | 75,048 |
| European (non-Finnish) | 8.47e-05% | 1,180,027 |

*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}

**ABCC3** population constraint: LOEUF 0.831, pLI 2.7122e-28, missense-Z 1.2504. *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 **145** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.29, 39% of residues very-high.

**4 experimental structure(s)** (PDB): [8HVH](https://www.rcsb.org/structure/8HVH), [8HW2](https://www.rcsb.org/structure/8HW2), [8HW4](https://www.rcsb.org/structure/8HW4), [8IZP](https://www.rcsb.org/structure/8IZP).

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

*Describes the biological roles of ABCC3 (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:** ABCC3's established molecular role includes ABC-type xenobiotic transporter activity.


### Pathways affected {#pathways}

ABCC3 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [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 |
| [Recycling of bile acids and salts](https://reactome.org/content/detail/R-HSA-159418) | curated |

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

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

**Biological process:** xenobiotic transmembrane transport, xenobiotic transport, leukotriene transport.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-04-10.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-04-10 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related ABCC3 variant pages (same residue, condition, or type): [ABCC3 p.Arg923Gln](/variant/abcc3-p-arg923gln), [ABCC3 p.Arg99Gln](/variant/abcc3-p-arg99gln), [ABCC3 p.His68Tyr](/variant/abcc3-p-his68tyr), [ABCC3 p.Ile794=](/variant/abcc3-p-ile794), [ABCC3 p.Leu1336=](/variant/abcc3-p-leu1336), [ABCC3 p.Leu1352Phe](/variant/abcc3-p-leu1352phe), [ABCC3 p.Ala100Asp](/variant/abcc3-p-ala100asp), [ABCC3 p.Ala100Ser](/variant/abcc3-p-ala100ser).

### 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 739697). 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.*