# NM_001206999.2(CIT):c.1121C>G (p.Pro374Arg)

https://sugi.bio/variant/cit-p-pro374arg

## Summary

**CIT p.Pro374Arg (c.1121C>G)** is classified **Uncertain significance** in CIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.7981); Rare (popmax 0.144%, mid); Associated with microcephaly 17, primary, autosomal recessive.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs200052993 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · rare (popmax 0.144%, mid)

## For patients & families {#patients}

This is a change in the CIT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to microcephaly 17, primary, autosomal recessive.

*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/0016186/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CIT](https://sugi.bio/atlas/gene/CIT/) |
| Protein change (HGVS p.) | p.Pro374Arg |
| Coding change (HGVS c.) | c.1121C>G |
| MANE Select transcript | [NM_001206999](https://www.ncbi.nlm.nih.gov/nuccore/NM_001206999) |
| dbSNP | [rs200052993](https://www.ncbi.nlm.nih.gov/snp/rs200052993/) |
| Variant type | single nucleotide variant |
| Location | chr12:119803380-119803380 (GRCh38) |
| ClinVar | [VCV1337123](https://www.ncbi.nlm.nih.gov/clinvar/variation/1337123/) |

**All HGVS expressions:** `NC_000012.11:g.120241184G>C`, `NC_000012.12:g.119803380G>C`, `NG_029792.1:g.78912C>G`, `NM_001206999.2:c.1121C>G`, `NM_007174.3:c.1121C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7981)
- REVEL 0.757 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.99 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.724, GERP 1.62, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. 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 0.96** across the covering region of the MANE Select transcript (119,785,026–119,876,168), spanning 91,142 bp. Chi-square p 0.38. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain, 9 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.144%** (mid) · FAF95 0.0715% · FAF99 0.0522% · 8/5,566 in the highest group · 106/1,566,938 alleles overall — rare (popmax 0.144%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.144% | 696 |
| Admixed American | 0.008% | 12,498 |
| European (non-Finnish) | 0.00706% | 14,160 |
| Remaining individuals (not grpmax-eligible) | 0.00665% | 15,048 |
| African / African-American | 0.00558% | 17,932 |
| East Asian | 0.00469% | 21,301 |
| Finnish (not grpmax-eligible) | 0.00159% | 63,034 |
| South Asian | 0.00118% | 84,874 |

*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}

**CIT** population constraint: LOEUF 0.353, pLI 1, missense-Z 5.1795. *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 agc-kinase c-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 69.75, 15% of residues very-high.

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

*Describes the biological roles of CIT (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:** CIT's established molecular role includes transcription coactivator binding. p.Pro374Arg falls in the agc-kinase c-terminal domain.


### Pathways affected {#pathways}

CIT participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | other |
| [RHO GTPases activate CIT](https://reactome.org/content/detail/R-HSA-5625900) | other |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | other |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | other |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | other |

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

**Molecular function:** transcription coactivator binding, protein kinase binding, PDZ domain binding, protein serine/threonine kinase inhibitor activity, scaffold protein binding.

**Biological process:** mitotic cytokinesis, positive regulation of cytokinesis, negative regulation of hippo signaling, neuron apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-14.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-15 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-14 |

## Associated conditions {#conditions}

[microcephaly 17, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-17-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 17, primary, autosomal recessive, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CIT variant pages (same residue, condition, or type): [CIT p.Pro374His](/variant/cit-p-pro374his), [CIT p.Pro374Ala](/variant/cit-p-pro374ala), [CIT p.Pro374Thr](/variant/cit-p-pro374thr), [CIT p.Arg220Ter](/variant/cit-p-arg220ter), [CIT p.Ala1144Thr](/variant/cit-p-ala1144thr), [CIT p.Ala244Val](/variant/cit-p-ala244val), [CIT p.Arg1633Cys](/variant/cit-p-arg1633cys), [CIT p.Arg23Trp](/variant/cit-p-arg23trp).

### 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 1337123). 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.*