# NM_001386298.1(CIC):c.5455C>T (p.Pro1819Ser)

https://sugi.bio/variant/cic-p-pro1819ser

## Summary

**CIC p.Pro1819Ser (c.5455C>T)** is classified **Conflicting classifications of pathogenicity** in CIC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0583); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs778737030 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the CIC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, 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.Pro1819Ser |
| Coding change (HGVS c.) | c.5455C>T |
| MANE Select transcript | [NM_001386298](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386298) |
| dbSNP | [rs778737030](https://www.ncbi.nlm.nih.gov/snp/rs778737030/) |
| Variant type | single nucleotide variant |
| Location | chr19:42291587-42291587 (GRCh38) |
| ClinVar | [VCV1033735](https://www.ncbi.nlm.nih.gov/clinvar/variation/1033735/) |

**All HGVS expressions:** `LRG_999:g.28051C>T`, `NC_000019.10:g.42291587C>T`, `NC_000019.9:g.42795739C>T`, `NG_042060.1:g.28051C>T`, `NM_001304815.2:c.5455C>T`, `NM_001379480.1:c.5455C>T`, `NM_001379482.1:c.5455C>T`, `NM_001379484.1:c.2728C>T`, `NM_001379485.1:c.2728C>T`, `NM_001386298.1:c.5455C>T`, `NM_015125.5:c.2728C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0583)
- REVEL 0.06 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 2.761, GERP 0.182, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P910S** vs ClinVar **P1819S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 19.37**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.01%** (amr) · FAF95 0.00428% · FAF99 0.00295% · 6/59,992 in the highest group · 7/1,612,852 alleles overall — ultra-rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 9,999 |
| European (non-Finnish) | 8.47e-05% | 1,179,984 |

*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 3/3, triplosensitivity 0/3. *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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-21.

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

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-21 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-21 |

## Associated conditions {#conditions}

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

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

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1033735). 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.*