# NM_000352.6(ABCC8):c.723C>T (p.His241=)

https://sugi.bio/variant/abcc8-p-his241

## Summary

**ABCC8 p.His241= (c.723C>T)** is classified **Conflicting classifications of pathogenicity** in ABCC8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-04-25). Ultra-rare (popmax 0.032%, afr); Associated with transient neonatal diabetes mellitus.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147276708 · 4 submitters · 5 linked conditions · ultra-rare (popmax 0.032%, 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 4 submitters, and is linked to transient neonatal diabetes mellitus.

*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 | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025170/index) · [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.His241= |
| Coding change (HGVS c.) | c.723C>T |
| MANE Select transcript | [NM_000352](https://www.ncbi.nlm.nih.gov/nuccore/NM_000352) |
| dbSNP | [rs147276708](https://www.ncbi.nlm.nih.gov/snp/rs147276708/) |
| Variant type | single nucleotide variant |
| Location | chr11:17461682-17461682 (GRCh38) |
| ClinVar | [VCV877362](https://www.ncbi.nlm.nih.gov/clinvar/variation/877362/) |

**All HGVS expressions:** `LRG_790:g.20221C>T`, `LRG_790t1:c.723C>T`, `LRG_790t2:c.723C>T`, `NC_000011.10:g.17461682G>A`, `NC_000011.9:g.17483229G>A`, `NG_008867.1:g.20221C>T`, `NM_000352.6:c.723C>T`, `NM_001287174.3:c.723C>T`, `NM_001351295.2:c.723C>T`, `NM_001351296.2:c.723C>T`, `NM_001351297.2:c.723C>T`, `NR_147094.2:n.792C>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 2.196, GERP -0.721, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.073**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.032%** (afr) · FAF95 0.022% · FAF99 0.0187% · 24/74,930 in the highest group · 24/1,614,114 alleles overall — ultra-rare (popmax 0.032%, afr).

*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 **241** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-04-25.

**Submitter consensus:** conflicting (4 Uncertain significance, 2 Likely benign, 1 Benign).

**Submission history:** 7 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Uncertain significance | criteria provided, single submitter | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-11 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-25 |

## Associated conditions {#conditions}

[transient neonatal diabetes mellitus](https://sugi.bio/atlas/disease/transient-neonatal-diabetes-mellitus/), [hyperinsulinemic hypoglycemia, familial, 1](https://sugi.bio/atlas/disease/hyperinsulinemic-hypoglycemia-familial-1/), [diabetes mellitus, transient neonatal, 2](https://sugi.bio/atlas/disease/diabetes-mellitus-transient-neonatal-2/), [maturity-onset diabetes of the young](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young/), [permanent neonatal diabetes mellitus](https://sugi.bio/atlas/disease/permanent-neonatal-diabetes-mellitus/).

**Reported phenotype names (ClinVar):** Transitory neonatal diabetes mellitus, Diabetes mellitus, transient neonatal, 2, Permanent neonatal diabetes mellitus, Hyperinsulinemic hypoglycemia, familial, 1, Maturity-onset diabetes of the young, not provided, Inborn genetic diseases, none provided, Transient neonatal diabetes mellitus, Maturity onset diabetes mellitus in young.

## Similar variants {#similar}

Related ABCC8 variant pages (same residue, condition, or type): [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), [ABCC8 c.1817+2T>C](/variant/abcc8-c-1817-plus-2t-c), [ABCC8 c.2041-21G>A](/variant/abcc8-c-2041-minus-21g-a).

### 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 877362). 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.*