# NM_001206999.2(CIT):c.1120C>G (p.Pro374Ala)

https://sugi.bio/variant/cit-p-pro374ala

## Summary

**CIT p.Pro374Ala (c.1120C>G)** is classified **Uncertain significance** in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.3921); Ultra-rare (popmax 0.0519%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0519%, eas)

## 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 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CIT](https://sugi.bio/atlas/gene/CIT/) |
| Protein change (HGVS p.) | p.Pro374Ala |
| Coding change (HGVS c.) | c.1120C>G |
| MANE Select transcript | [NM_001206999](https://www.ncbi.nlm.nih.gov/nuccore/NM_001206999) |
| Variant type | single nucleotide variant |
| Location | chr12:119803381-119803381 (GRCh38) |
| ClinVar | [VCV4003127](https://www.ncbi.nlm.nih.gov/clinvar/variation/4003127/) |

**All HGVS expressions:** `NC_000012.11:g.120241185G>C`, `NC_000012.12:g.119803381G>C`, `NG_029792.1:g.78911C>G`, `NG_029792.2:g.78939C>G`, `NM_001206999.2:c.1120C>G`, `NM_007174.3:c.1120C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3921) — no call either way
- REVEL 0.425 (indeterminate)
- SaProt LLR -9.974 (tolerated)
- SpliceAI predicts **acceptor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.602, GERP 1.62, phastCons 1 — highly conserved
- CADD: **PHRED 27.8**. 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 **0.07**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**. Largest is acceptor gain, 8 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 **0.0519%** (eas) · FAF95 0.0351% · FAF99 0.0296% · 22/42,386 in the highest group · 29/1,558,912 alleles overall — ultra-rare (popmax 0.0519%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0519% | 1,927 |
| African / African-American | 0.00843% | 11,859 |
| South Asian | 0.00119% | 84,052 |

*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.Pro374Ala 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-02.

**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 | 2025-04-02 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CIT variant pages (same residue, condition, or type): [CIT p.Pro374Thr](/variant/cit-p-pro374thr), [CIT p.Pro374Arg](/variant/cit-p-pro374arg), [CIT p.Pro374His](/variant/cit-p-pro374his), [CIT p.Arg1178Ter](/variant/cit-p-arg1178ter), [CIT c.4168+5G>A](/variant/cit-c-4168-plus-5g-a), [CIT p.Ala1527Val](/variant/cit-p-ala1527val), [CIT p.Ala495Ser](/variant/cit-p-ala495ser), [CIT p.Ala8Val](/variant/cit-p-ala8val).

### 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 4003127). 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.*