# NM_001393997.1(CCAR2):c.1116C>T (p.Asp372=)

https://sugi.bio/variant/ccar2-p-asp372

## Summary

**CCAR2 p.Asp372= (c.1116C>T)** is classified **Likely benign** in CCAR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-18). Very rare (popmax 0.00834%, amr); Associated with CCAR2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs1246249006 · 1 submitter · 1 linked condition · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the CCAR2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CCAR2-related disorder.

*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 | [CCAR2](https://sugi.bio/atlas/gene/CCAR2/) |
| Protein change (HGVS p.) | p.Asp372= |
| Coding change (HGVS c.) | c.1116C>T |
| MANE Select transcript | [NM_001393997](https://www.ncbi.nlm.nih.gov/nuccore/NM_001393997) |
| dbSNP | [rs1246249006](https://www.ncbi.nlm.nih.gov/snp/rs1246249006/) |
| Variant type | single nucleotide variant |
| Location | chr8:22614912-22614912 (GRCh38) |
| ClinVar | [VCV3058620](https://www.ncbi.nlm.nih.gov/clinvar/variation/3058620/) |

**All HGVS expressions:** `NC_000008.10:g.22472425C>T`, `NC_000008.11:g.22614912C>T`, `NM_001363068.2:c.1116C>T`, `NM_001363069.2:c.1116C>T`, `NM_001393997.1:c.1116C>T`, `NM_021174.6:c.1116C>T`, `NR_033902.2:n.1240C>T`

## 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 0.865, GERP 0.865, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 16.25**. 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 (C>G, Δ0.21 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 **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,962 in the highest group · 8/1,613,574 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,992 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,214 |
| European (non-Finnish) | 8.47e-05% | 1,179,966 |

*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}

**CCAR2** population constraint: LOEUF 0.288, pLI 1, missense-Z 0.82873. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.61, 37% of residues very-high.

**1 experimental structure(s)** (PDB): [8EZ6](https://www.rcsb.org/structure/8EZ6).

## What this gene does {#gene-function}

*Describes the biological roles of CCAR2 (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:** CCAR2's established molecular role includes RNA polymerase II complex binding.


### Pathways affected {#pathways}

CCAR2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II complex binding, RNA binding, enzyme inhibitor activity, enzyme binding.

**Biological process:** regulation of DNA-templated transcription, RNA splicing, response to UV, negative regulation of cell growth, regulation of protein stability, negative regulation of proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-02-18.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-02-18 |

## Associated conditions {#conditions}

[CCAR2-related disorder](https://sugi.bio/atlas/disease/ccar2-related-disorder/).

**Reported phenotype names (ClinVar):** CCAR2-related disorder, CCAR2-related condition.

## Similar variants {#similar}

Related CCAR2 variant pages (same residue, condition, or type): [CCAR2 c.150+8C>G](/variant/ccar2-c-150-plus-8c-g), [CCAR2 c.1609-5A>G](/variant/ccar2-c-1609-minus-5a-g), [CCAR2 c.2522-3C>T](/variant/ccar2-c-2522-minus-3c-t), [CCAR2 p.Ala406=](/variant/ccar2-p-ala406), [CCAR2 p.Ala819=](/variant/ccar2-p-ala819), [CCAR2 p.Arg418Gln](/variant/ccar2-p-arg418gln), [CCAR2 p.Asp292=](/variant/ccar2-p-asp292), [CCAR2 p.Asp469=](/variant/ccar2-p-asp469).

### 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 3058620). 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.*