# NM_001386298.1(CIC):c.7510T>C (p.Ser2504Pro)

https://sugi.bio/variant/cic-p-ser2504pro

## Summary

**CIC p.Ser2504Pro (c.7510T>C)** is classified **Conflicting classifications of pathogenicity** in CIC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2019-05-28). AlphaMissense: likely benign (0.0898); Common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele; Associated with intellectual developmental disorder, autosomal dominant 45.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs745695673 · 4 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele

## 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.Ser2504Pro |
| Coding change (HGVS c.) | c.7510T>C |
| MANE Select transcript | [NM_005984](https://www.ncbi.nlm.nih.gov/nuccore/NM_005984) (variant reported on NM_001386298) |
| dbSNP | [rs745695673](https://www.ncbi.nlm.nih.gov/snp/rs745695673/) |
| Variant type | single nucleotide variant |
| Location | chr19:42295147-42295147 (GRCh38) |
| ClinVar | [VCV252693](https://www.ncbi.nlm.nih.gov/clinvar/variation/252693/) |

**All HGVS expressions:** `LRG_999:g.31611T>C`, `NC_000019.10:g.42295147T>C`, `NC_000019.9:g.42799299T>C`, `NG_042060.1:g.31611T>C`, `NM_001304815.2:c.7510T>C`, `NM_001379480.1:c.7507T>C`, `NM_001379482.1:c.7507T>C`, `NM_001379484.1:c.4777T>C`, `NM_001379485.1:c.4774T>C`, `NM_001386298.1:c.7510T>C`, `NM_015125.5:c.4783T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0898)
- REVEL 0.293 (indeterminate)
- Conservation: phyloP 3.39, GERP 1.36, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S1595P** vs ClinVar **S2504P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 20.6**. 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 **7.81%** (afr) · FAF95 7.49% · FAF99 7.36% · 1,583/20,278 in the highest group · 11,004/313,768 alleles overall — common (popmax 7.81%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 14.9% | 7 |
| African / African-American (grpmax) | 7.81% | 13 |
| Admixed American | 4.08% | 25 |
| European (non-Finnish) | 3.62% | 28 |
| Ashkenazi Jewish (not grpmax-eligible) | 3.39% | 29 |
| Finnish (not grpmax-eligible) | 2.96% | 34 |
| Middle Eastern | 2.81% | 36 |
| Remaining individuals (not grpmax-eligible) | 2.32% | 43 |
| South Asian | 1.55% | 64 |
| East Asian | 1.55% | 65 |

Amish 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2019-05-28.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2015–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-10-02 |

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

## 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 252693). 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.*