# NM_001386298.1(CIC):c.5519T>G (p.Met1840Arg)

https://sugi.bio/variant/cic-p-met1840arg

## Summary

**CIC p.Met1840Arg (c.5519T>G)** is classified **Uncertain significance** in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: ambiguous (0.3964); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750399330 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CIC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [CIC](https://sugi.bio/atlas/gene/CIC/) |
| Protein change (HGVS p.) | p.Met1840Arg |
| Coding change (HGVS c.) | c.5519T>G |
| MANE Select transcript | [NM_005984](https://www.ncbi.nlm.nih.gov/nuccore/NM_005984) (variant reported on NM_001386298) |
| dbSNP | [rs750399330](https://www.ncbi.nlm.nih.gov/snp/rs750399330/) |
| Variant type | single nucleotide variant |
| Location | chr19:42291651-42291651 (GRCh38) |
| ClinVar | [VCV2298948](https://www.ncbi.nlm.nih.gov/clinvar/variation/2298948/) |

**All HGVS expressions:** `LRG_999:g.28115T>G`, `LRG_999t1:c.2792T>G`, `LRG_999t2:c.5519T>G`, `NC_000019.10:g.42291651T>G`, `NC_000019.9:g.42795803T>G`, `NG_042060.1:g.28115T>G`, `NM_001304815.2:c.5519T>G`, `NM_001379480.1:c.5519T>G`, `NM_001379482.1:c.5519T>G`, `NM_001379483.1:c.5519T>G`, `NM_001379484.1:c.2792T>G`, `NM_001379485.1:c.2792T>G`, `NM_001386298.1:c.5519T>G`, `NM_015125.5:c.2792T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3964) — no call either way
- REVEL 0.235 (benign-leaning)
- SpliceAI predicts **donor gain** (Δ 0.85) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.943, GERP 1.37, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **M931R** vs ClinVar **M1840R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 32.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.85**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.85**.
- Pangolin: Δ**0.76** (gain), gain 0.76 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,992 in the highest group · 4/1,612,824 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,233 |
| Admixed American (grpmax) | 0.00167% | 59,992 |
| African / African-American | 0.00133% | 74,916 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-11.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CIC variant pages (same residue, condition, or type): [CIC p.Met1840Ile](/variant/cic-p-met1840ile), [CIC c.2795-2056C>T](/variant/cic-c-2795-minus-2056c-t), [CIC p.Ala1228Val](/variant/cic-p-ala1228val), [CIC p.Ala1445Gly](/variant/cic-p-ala1445gly), [CIC p.Ala1750Val](/variant/cic-p-ala1750val), [CIC p.Ala1975Gly](/variant/cic-p-ala1975gly), [CIC p.Ala2463Thr](/variant/cic-p-ala2463thr), [CIC p.Arg1205Trp](/variant/cic-p-arg1205trp).

### 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 2298948). 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.*