# NM_000352.6(ABCC8):c.1812A>T (p.Leu604=)

https://sugi.bio/variant/abcc8-p-leu604

## Summary

**ABCC8 p.Leu604= (c.1812A>T)** is classified **Likely benign** in ABCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-24). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs2496687952 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCC8 gene that is classified as likely 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 | [ABCC8](https://sugi.bio/atlas/gene/ABCC8/) |
| Protein change (HGVS p.) | p.Leu604= |
| Coding change (HGVS c.) | c.1812A>T |
| MANE Select transcript | [NM_000352](https://www.ncbi.nlm.nih.gov/nuccore/NM_000352) |
| dbSNP | [rs2496687952](https://www.ncbi.nlm.nih.gov/snp/rs2496687952/) |
| Variant type | single nucleotide variant |
| Location | chr11:17430819-17430819 (GRCh38) |
| ClinVar | [VCV2816433](https://www.ncbi.nlm.nih.gov/clinvar/variation/2816433/) |

**All HGVS expressions:** `LRG_790:g.51084A>T`, `LRG_790t1:c.1812A>T`, `LRG_790t2:c.1812A>T`, `NC_000011.10:g.17430819T>A`, `NC_000011.9:g.17452366T>A`, `NG_008867.1:g.51084A>T`, `NM_000352.6:c.1812A>T`, `NM_001287174.3:c.1812A>T`, `NM_001351295.2:c.1812A>T`, `NM_001351296.2:c.1809A>T`, `NM_001351297.2:c.1809A>T`, `NR_147094.2:n.1878A>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 -1.512, GERP -4.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.519**. 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 (T>C, Δ0.92 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ABCC8** population constraint: LOEUF 0.829, pLI 9.5344e-33, missense-Z 2.8451; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **pulmonary arterial hypertension** — Moderate (AD)
- **hyperinsulinism** — Definitive (AD)
- **hyperinsulinemic hypoglycemia, familial, 1** — Definitive (AR)
- **monogenic diabetes** — Definitive (SD)

## Protein context {#protein}

Residue **604** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 82.56, 42% of residues very-high.

**8 experimental structure(s)** (PDB): [6C3O](https://www.rcsb.org/structure/6C3O), [6C3P](https://www.rcsb.org/structure/6C3P), [7S5V](https://www.rcsb.org/structure/7S5V), [7S5X](https://www.rcsb.org/structure/7S5X), [7S5Y](https://www.rcsb.org/structure/7S5Y), [7S5Z](https://www.rcsb.org/structure/7S5Z).

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

*Describes the biological roles of ABCC8 (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:** ABCC8's established molecular role includes potassium channel activity. In Reactome, ABCC8 is annotated in disease pathway(s) including **Defective ABCC8 can cause hypo- and hyper-glycemias**.

**Disease mechanism (Reactome):** ABCC8 loss or alteration is curated in [Defective ABCC8 can cause hypo- and hyper-glycemias](https://reactome.org/content/detail/R-HSA-5683177).

### Pathways affected {#pathways}

ABCC8 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCC8 can cause hypo- and hyper-glycemias](https://reactome.org/content/detail/R-HSA-5683177) | curated |
| [ATP sensitive Potassium channels](https://reactome.org/content/detail/R-HSA-1296025) | curated |
| [Regulation of insulin secretion](https://reactome.org/content/detail/R-HSA-422356) | curated |

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

**Molecular function:** potassium channel activity, ATPase-coupled monoatomic cation transmembrane transporter activity, transmembrane transporter binding.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-24.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-24 |

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

## Same-residue context {#hotspot}

Residue **604** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ABCC8 p.Leu604fs](/variant/abcc8-p-leu604fs), [ABCC8 p.Leu604_Val605insTer](/variant/abcc8-p-leu604-val605inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCC8 variant pages (same residue, condition, or type): [ABCC8 p.Leu604_Val605insTer](/variant/abcc8-p-leu604-val605inster), [ABCC8 p.Leu604fs](/variant/abcc8-p-leu604fs), [ABCC8 c.1176+2T>C](/variant/abcc8-c-1176-plus-2t-c), [ABCC8 c.1333-1013A>G](/variant/abcc8-c-1333-minus-1013a-g), [ABCC8 c.148+1G>A](/variant/abcc8-c-148-plus-1g-a), [ABCC8 c.148+2T>G](/variant/abcc8-c-148-plus-2t-g), [ABCC8 c.1630+1G>A](/variant/abcc8-c-1630-plus-1g-a), [ABCC8 c.1630+1G>T](/variant/abcc8-c-1630-plus-1g-t).

### 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 2816433). 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.*