# NM_018237.4(CCAR1):c.1121C>T (p.Pro374Leu)

https://sugi.bio/variant/ccar1-p-pro374leu

## Summary

**CCAR1 p.Pro374Leu (c.1121C>T)** is classified **Uncertain significance** in CCAR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-17). AlphaMissense: likely benign (0.0775); Very rare (popmax 0.00503%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2056367512 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00503%, amr)

## For patients & families {#patients}

This is a change in the CCAR1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CCAR1](https://sugi.bio/atlas/gene/CCAR1/) |
| Protein change (HGVS p.) | p.Pro374Leu |
| Coding change (HGVS c.) | c.1121C>T |
| MANE Select transcript | [NM_018237](https://www.ncbi.nlm.nih.gov/nuccore/NM_018237) |
| dbSNP | [rs2056367512](https://www.ncbi.nlm.nih.gov/snp/rs2056367512/) |
| Variant type | single nucleotide variant |
| Location | chr10:68753854-68753854 (GRCh38) |
| ClinVar | [VCV2516524](https://www.ncbi.nlm.nih.gov/clinvar/variation/2516524/) |

**All HGVS expressions:** `NC_000010.10:g.70513611C>T`, `NC_000010.11:g.68753854C>T`, `NM_001282959.2:c.1076C>T`, `NM_001282960.2:c.1076C>T`, `NM_018237.4:c.1121C>T`, `NR_104262.2:n.1221C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0775)
- REVEL 0.063 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.223 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.128, GERP 1.35, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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.*
- Regional missense constraint: **o/e 0.71** across the covering region of the MANE Select transcript (68,722,505–68,766,017), spanning 43,512 bp. Chi-square p 4.8e-18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.27 acceptor gain), 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 **0.00503%** (amr) · FAF95 0.00133% · FAF99 0.00067% · 3/59,698 in the highest group · 4/1,608,158 alleles overall — very rare (popmax 0.00503%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00503% | 19,899 |
| European (non-Finnish) | 8.51e-05% | 1,175,563 |

*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}

**CCAR1** population constraint: LOEUF 0.651, pLI 4.0077e-06, missense-Z 3.2778. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **374** lies in the 'interaction with gata2' region.

AlphaFold model confidence (whole protein): pLDDT 69.55, 38% of residues very-high.

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

*Describes the biological roles of CCAR1 (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:** CCAR1's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Pro374Leu falls in the interaction with gata2 region. In Reactome, CCAR1 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CCAR1 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CCAR1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription coactivator activity, transcription corepressor activity, RNA binding.

**Biological process:** positive regulation of cell population proliferation, positive regulation of cell migration, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-17.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-17 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CCAR1 variant pages (same residue, condition, or type): [CCAR1 c.1625+1G>A](/variant/ccar1-c-1625-plus-1g-a), [CCAR1 p.Ala2Val](/variant/ccar1-p-ala2val), [CCAR1 p.Ala499Asp](/variant/ccar1-p-ala499asp), [CCAR1 p.Ala878Ser](/variant/ccar1-p-ala878ser), [CCAR1 p.Arg300Gln](/variant/ccar1-p-arg300gln), [CCAR1 p.Arg307Thr](/variant/ccar1-p-arg307thr), [CCAR1 p.Arg327His](/variant/ccar1-p-arg327his), [CCAR1 p.Arg340Leu](/variant/ccar1-p-arg340leu).

### 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 2516524). 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.*