# NM_001386298.1(CIC):c.2363del (p.Pro788fs)

https://sugi.bio/variant/cic-p-pro788fs

## Summary

**CIC p.Pro788fs (c.2363del)** is classified **Pathogenic/Likely pathogenic** in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-15). No allele count reported in gnomAD v4.1 (AN 399,192); Associated with intellectual developmental disorder, autosomal dominant 45.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2513612309 · 2 submitters · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 399,192)

## For patients & families {#patients}

This is a change in the CIC gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to intellectual developmental disorder, autosomal dominant 45.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025658/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CIC](https://sugi.bio/atlas/gene/CIC/) |
| Protein change (HGVS p.) | p.Pro788fs |
| Coding change (HGVS c.) | c.2363del |
| MANE Select transcript | [NM_005984](https://www.ncbi.nlm.nih.gov/nuccore/NM_005984) (variant reported on NM_001386298) |
| dbSNP | [rs2513612309](https://www.ncbi.nlm.nih.gov/snp/rs2513612309/) |
| Variant type | Deletion |
| Location | chr19:42274142-42274142 (GRCh38) |
| ClinVar | [VCV3068400](https://www.ncbi.nlm.nih.gov/clinvar/variation/3068400/) |

**All HGVS expressions:** `LRG_999:g.10610del`, `LRG_999t2:c.2363del`, `NC_000019.10:g.42274146del`, `NC_000019.9:g.42778298del`, `NG_042060.1:g.10610del`, `NM_001304815.2:c.2363del`, `NM_001379480.1:c.2363del`, `NM_001379482.1:c.2363del`, `NM_001379483.1:c.2363delC`, `NM_001386298.1:c.2363del`

## 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 -0.126, GERP -2.76, phastCons 0.464 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- 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: **no allele count reported in gnomAD v4.1 (AN 399,192)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CIC** population constraint: ClinGen dosage — haploinsufficiency 3, 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):

- **complex neurodevelopmental disorder** — Definitive (AD)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.09, 0% of residues very-high.

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

*Describes the biological roles of CIC (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:** CIC's established molecular role includes tricarboxylic acid transmembrane transporter activity.


### Pathways affected {#pathways}

CIC participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Organic anion transport by SLC5/17/25 transporters](https://reactome.org/content/detail/R-HSA-428643) | curated |

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

**Molecular function:** tricarboxylic acid transmembrane transporter activity, citrate secondary active transmembrane transporter activity.

**Biological process:** mitochondrial citrate transmembrane transport, negative regulation of ferroptosis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-15.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| MVZ Medizinische Genetik Mainz | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-08 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-15 |

## Associated conditions {#conditions}

[intellectual developmental disorder, autosomal dominant 45](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-autosomal-dominant-45/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 45, MENTAL RETARDATION, AUTOSOMAL DOMINANT 45, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 45.

## Similar variants {#similar}

Related CIC variant pages (same residue, condition, or type): [CIC p.Ala1694fs](/variant/cic-p-ala1694fs), [CIC p.Ala1809fs](/variant/cic-p-ala1809fs), [CIC p.Ala2056fs](/variant/cic-p-ala2056fs), [CIC p.Asp38fs](/variant/cic-p-asp38fs), [CIC p.Gln2115fs](/variant/cic-p-gln2115fs), [CIC p.Gln894fs](/variant/cic-p-gln894fs), [CIC p.Glu103fs](/variant/cic-p-glu103fs), [CIC p.Gly544fs](/variant/cic-p-gly544fs).

### 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 3068400). 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.*