# NM_000352.6(ABCC8):c.1634del (p.Phe545fs)

https://sugi.bio/variant/abcc8-p-phe545fs

## Summary

**ABCC8 p.Phe545fs (c.1634del)** is classified **Pathogenic** in ABCC8 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-05-07). Very rare (popmax 0.00196%, amr); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1260178539 · 9 submitters · 6 linked conditions · very rare (popmax 0.00196%, amr)

## For patients & families {#patients}

This is a change in the ABCC8 gene that is considered disease-causing, submitted by 9 submitters, and is linked to Inborn genetic diseases.

*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.Phe545fs |
| Coding change (HGVS c.) | c.1634del |
| MANE Select transcript | [NM_000352](https://www.ncbi.nlm.nih.gov/nuccore/NM_000352) |
| dbSNP | [rs1260178539](https://www.ncbi.nlm.nih.gov/snp/rs1260178539/) |
| Variant type | Deletion |
| Location | chr11:17432241-17432241 (GRCh38) |
| ClinVar | [VCV446765](https://www.ncbi.nlm.nih.gov/clinvar/variation/446765/) |

**All HGVS expressions:** `LRG_790:g.49662del`, `LRG_790t1:c.1634del`, `LRG_790t2:c.1634del`, `NC_000011.10:g.17432244del`, `NC_000011.9:g.17453791del`, `NG_008867.1:g.49662del`, `NM_000352.3:c.1634delT`, `NM_000352.6:c.1634del`, `NM_001287174.3:c.1634del`, `NM_001351295.2:c.1634del`, `NM_001351296.2:c.1631del`, `NM_001351297.2:c.1631del`, `NR_147094.2:n.1700del`

## 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 7.457, GERP 2.38, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.829, pLI 9.5344e-33. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 39**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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 **0.00196%** (amr) · 1/51,052 in the highest group · 1/1,400,002 alleles overall — very rare (popmax 0.00196%, amr).

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

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. p.Phe545fs falls in the abc transmembrane type-1 1 domain. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-07.

**Submitter consensus:** conflicting (8 Pathogenic, 2 Uncertain risk allele).

**Submission history:** 10 submissions (2017–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-05-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-28 |
| Natera, Inc. | Pathogenic | no assertion criteria provided | clinical testing | 2021-08-23 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Pathogenic | criteria provided, single submitter | curation | 2023-08-16 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-17 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-11-23 |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Uncertain risk allele | flagged submission | research | 2024-05-27 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-08-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [type 2 diabetes mellitus](https://sugi.bio/atlas/disease/type-2-diabetes-mellitus/), [hyperinsulinemic hypoglycemia, familial, 1](https://sugi.bio/atlas/disease/hyperinsulinemic-hypoglycemia-familial-1/), [neonatal diabetes mellitus](https://sugi.bio/atlas/disease/neonatal-diabetes-mellitus/), [familial hyperinsulinism](https://sugi.bio/atlas/disease/familial-hyperinsulinism/), [maturity-onset diabetes of the young](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Hyperinsulinemic hypoglycemia, familial, 1, Familial hyperinsulinism, Maturity-onset diabetes of the young, Hereditary hyperinsulinism, Type 2 diabetes mellitus, Neonatal diabetes mellitus, none provided, Type II diabetes mellitus.

## Similar variants {#similar}

Related ABCC8 variant pages (same residue, condition, or type): [ABCC8 p.Ala269fs](/variant/abcc8-p-ala269fs), [ABCC8 p.Gln19fs](/variant/abcc8-p-gln19fs), [ABCC8 p.Gln273fs](/variant/abcc8-p-gln273fs), [ABCC8 p.Gln632fs](/variant/abcc8-p-gln632fs), [ABCC8 p.His627fs](/variant/abcc8-p-his627fs), [ABCC8 p.Ile450fs](/variant/abcc8-p-ile450fs), [ABCC8 p.Ile550fs](/variant/abcc8-p-ile550fs), [ABCC8 p.Leu1170fs](/variant/abcc8-p-leu1170fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 446765). 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.*