# NM_000352.6(ABCC8):c.1858C>T (p.Arg620Cys)

https://sugi.bio/variant/abcc8-p-arg620cys

## Summary

**ABCC8 p.Arg620Cys (c.1858C>T)** is classified **Conflicting classifications of pathogenicity** in ABCC8 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1035); Rare (popmax 0.921%, afr); Associated with monogenic diabetes.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs58241708 · 13 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.921%, afr)

## For patients & families {#patients}

This is a change in the ABCC8 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 13 submitters, and is linked to monogenic diabetes.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**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.Arg620Cys |
| Coding change (HGVS c.) | c.1858C>T |
| MANE Select transcript | [NM_000352](https://www.ncbi.nlm.nih.gov/nuccore/NM_000352) |
| dbSNP | [rs58241708](https://www.ncbi.nlm.nih.gov/snp/rs58241708/) |
| Variant type | single nucleotide variant |
| Location | chr11:17428630-17428630 (GRCh38) |
| ClinVar | [VCV210071](https://www.ncbi.nlm.nih.gov/clinvar/variation/210071/) |

**All HGVS expressions:** `LRG_790:g.53273C>T`, `LRG_790t1:c.1858C>T`, `LRG_790t2:c.1858C>T`, `NC_000011.10:g.17428630G>A`, `NC_000011.9:g.17450177G>A`, `NG_008867.1:g.53273C>T`, `NM_000352.6:c.1858C>T`, `NM_001287174.3:c.1858C>T`, `NM_001351295.2:c.1858C>T`, `NM_001351296.2:c.1855C>T`, `NM_001351297.2:c.1855C>T`, `NR_147094.2:n.1924C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1035)
- REVEL 0.445 (indeterminate)
- SaProt LLR -7.153 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.063, GERP 2.06, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.0**. 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.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (17,392,994–17,476,776), spanning 83,782 bp. Chi-square p 1.4e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 10 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.921%** (afr) · FAF95 0.864% · FAF99 0.841% · 691/75,046 in the highest group · 801/1,613,976 alleles overall — rare (popmax 0.921%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.921% | 109 |
| Admixed American | 0.0566% | 1,765 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.054% | 1,851 |
| Remaining individuals (not grpmax-eligible) | 0.0464% | 2,155 |
| Middle Eastern | 0.033% | 3,031 |
| South Asian | 0.0132% | 7,590 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,816 |
| European (non-Finnish) | 0.00136% | 73,752 |

*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 **620** lies in a UniProt-annotated variant site (in hhf1).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (7 Likely benign, 3 Benign, 3 Uncertain significance).

**Submission history:** 13 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2015-03-19 |
| Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Benign | criteria provided, single submitter | research | 2018-12-07 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2019-12-24 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-03 |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2023-08-22 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-04 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-01-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-08 |

## Associated conditions {#conditions}

[monogenic diabetes](https://sugi.bio/atlas/disease/monogenic-diabetes/), [hyperinsulinemic hypoglycemia, familial, 1](https://sugi.bio/atlas/disease/hyperinsulinemic-hypoglycemia-familial-1/).

**Reported phenotype names (ClinVar):** Monogenic diabetes, not specified, Hyperinsulinemic hypoglycemia, familial, 1, not provided, Hereditary hyperinsulinism, AllHighlyPenetrant, none provided, Persistent hyperinsulinemic hypoglycemia of infancy, Persistent Hyperinsulinemia Hypoglycemia of Infancy, HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS.

## Same-residue context {#hotspot}

Residue **620** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCC8 p.Arg620fs](/variant/abcc8-p-arg620fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCC8 variant pages (same residue, condition, or type): [ABCC8 p.Arg620fs](/variant/abcc8-p-arg620fs), [ABCC8 p.Arg620=](/variant/abcc8-p-arg620), [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 210071). 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.*