# NM_001386298.1(CIC):c.6018T>C (p.Ser2006=)

https://sugi.bio/variant/cic-p-ser2006

## Summary

**CIC p.Ser2006= (c.6018T>C)** is classified **Benign/Likely benign** in CIC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.04%, sas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs142078348 · 5 submitters · low-frequency (popmax 1.04%, sas)

## For patients & families {#patients}

This is a change in the CIC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters.

*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.Ser2006= |
| Coding change (HGVS c.) | c.6018T>C |
| MANE Select transcript | [NM_005984](https://www.ncbi.nlm.nih.gov/nuccore/NM_005984) (variant reported on NM_001386298) |
| dbSNP | [rs142078348](https://www.ncbi.nlm.nih.gov/snp/rs142078348/) |
| Variant type | single nucleotide variant |
| Location | chr19:42292681-42292681 (GRCh38) |
| ClinVar | [VCV735963](https://www.ncbi.nlm.nih.gov/clinvar/variation/735963/) |

**All HGVS expressions:** `LRG_999:g.29145T>C`, `LRG_999t1:c.3291T>C`, `NC_000019.10:g.42292681T>C`, `NC_000019.9:g.42796833T>C`, `NG_042060.1:g.29145T>C`, `NM_001304815.2:c.6018T>C`, `NM_001379480.1:c.6018T>C`, `NM_001379482.1:c.6018T>C`, `NM_001379484.1:c.3291T>C`, `NM_001379485.1:c.3291T>C`, `NM_001386298.1:c.6018T>C`, `NM_015125.5:c.3291T>C`

## 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 -3.896, GERP -0.253 — fast-evolving / accelerated position
- CADD: **PHRED 2.516**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.40 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.04%** (sas) · FAF95 0.988% · FAF99 0.966% · 950/91,086 in the highest group · 1,918/1,613,814 alleles overall — low-frequency (popmax 1.04%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.04% | 96 |
| Middle Eastern | 0.528% | 189 |
| Remaining individuals (not grpmax-eligible) | 0.174% | 573 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.128% | 779 |
| Admixed American | 0.0666% | 1,500 |
| European (non-Finnish) | 0.0618% | 1,619 |
| African / African-American | 0.02% | 5,002 |
| Finnish (not grpmax-eligible) | 0.0047% | 21,263 |
| East Asian | 0.00446% | 22,439 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (3 Benign, 2 Likely benign).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-04-10 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-23 |

**Reported phenotype names (ClinVar):** not provided, CIC-related disorder, not specified, AllHighlyPenetrant, CIC-related condition, none provided.

## Similar variants {#similar}

Related CIC variant pages (same residue, condition, or type): [CIC p.Ser2006Cys](/variant/cic-p-ser2006cys), [CIC c.3179+1G>A](/variant/cic-c-3179-plus-1g-a), [CIC c.3179+1G>T](/variant/cic-c-3179-plus-1g-t), [CIC c.5903-2A>G](/variant/cic-c-5903-minus-2a-g), [CIC p.Asn1136Ser](/variant/cic-p-asn1136ser), [CIC p.Gln1134Ter](/variant/cic-p-gln1134ter), [CIC p.Gln1799Ter](/variant/cic-p-gln1799ter), [SLC25A1 c.821+1G>A](/variant/slc25a1-c-821-plus-1g-a).

### 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 735963). 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.*