# NM_001386298.1(CIC):c.4673C>T (p.Ser1558Phe)

https://sugi.bio/variant/cic-p-ser1558phe

## Summary

**CIC p.Ser1558Phe (c.4673C>T)** is classified **Conflicting classifications of pathogenicity** in CIC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.1524); Ultra-rare (popmax 0.0118%, nfe); Associated with intellectual developmental disorder, autosomal dominant 45.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs758817184 · 4 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0118%, nfe)

## 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 4 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.Ser1558Phe |
| Coding change (HGVS c.) | c.4673C>T |
| MANE Select transcript | [NM_005984](https://www.ncbi.nlm.nih.gov/nuccore/NM_005984) (variant reported on NM_001386298) |
| dbSNP | [rs758817184](https://www.ncbi.nlm.nih.gov/snp/rs758817184/) |
| Variant type | single nucleotide variant |
| Location | chr19:42290714-42290714 (GRCh38) |
| ClinVar | [VCV2440078](https://www.ncbi.nlm.nih.gov/clinvar/variation/2440078/) |

**All HGVS expressions:** `LRG_999:g.27178C>T`, `LRG_999t1:c.1946C>T`, `LRG_999t2:c.4673C>T`, `NC_000019.10:g.42290714C>T`, `NC_000019.9:g.42794866C>T`, `NG_042060.1:g.27178C>T`, `NG_141491.1:g.801C>T`, `NM_001304815.2:c.4673C>T`, `NM_001379480.1:c.4673C>T`, `NM_001379482.1:c.4673C>T`, `NM_001379483.1:c.4673C>T`, `NM_001379484.1:c.1946C>T`, `NM_001379485.1:c.1946C>T`, `NM_001386298.1:c.4673C>T`, `NM_015125.5:c.1946C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1524)
- REVEL 0.112 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- Conservation: phyloP 3.3, GERP 0.397, phastCons 0.986 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S649F** vs ClinVar **S1558F**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 19.41**. 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 **0.0118%** (nfe) · FAF95 0.0102% · FAF99 0.00956% · 139/1,179,750 in the highest group · 144/1,612,384 alleles overall — ultra-rare (popmax 0.0118%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0118% | 8,487 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,592 |
| African / African-American | 0.00133% | 74,920 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-08.

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

**Submission history:** 4 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-29 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-08 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-21 |

## 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, not provided, not specified, MENTAL RETARDATION, AUTOSOMAL DOMINANT 45, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 45, none provided, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **1558** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CIC p.Ser1558fs](/variant/cic-p-ser1558fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## 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 p.Ala1761Val](/variant/cic-p-ala1761val), [CIC p.Ala2064Thr](/variant/cic-p-ala2064thr), [CIC p.Ala2463Thr](/variant/cic-p-ala2463thr).

### 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 2440078). 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.*