# NM_001206999.2(CIT):c.1125C>T (p.Phe375=)

https://sugi.bio/variant/cit-p-phe375

## Summary

**CIT p.Phe375= (c.1125C>T)** is classified **Uncertain significance** in CIT (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-11). Ultra-rare (popmax 0.0351%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs200757503 · 2 submitters · ultra-rare (popmax 0.0351%, 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 2 submitters.

*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.Phe375= |
| Coding change (HGVS c.) | c.1125C>T |
| MANE Select transcript | [NM_001206999](https://www.ncbi.nlm.nih.gov/nuccore/NM_001206999) |
| dbSNP | [rs200757503](https://www.ncbi.nlm.nih.gov/snp/rs200757503/) |
| Variant type | single nucleotide variant |
| Location | chr12:119803376-119803376 (GRCh38) |
| ClinVar | [VCV2173063](https://www.ncbi.nlm.nih.gov/clinvar/variation/2173063/) |

**All HGVS expressions:** `NC_000012.11:g.120241180G>A`, `NC_000012.12:g.119803376G>A`, `NG_029792.1:g.78916C>T`, `NG_029792.2:g.78944C>T`, `NM_001206999.1:c.1125C>T`, `NM_001206999.2:c.1125C>T`, `NM_007174.3:c.1125C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.602, GERP 1.62, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.67**. 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 deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Pangolin: Δ**0.29** (gain), gain 0.29 / loss 0.24. SpliceAI calls loss. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0351%** (eas) · FAF95 0.0216% · FAF99 0.0174% · 15/42,710 in the highest group · 33/1,570,490 alleles overall — ultra-rare (popmax 0.0351%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0351% | 2,847 |
| Remaining individuals (not grpmax-eligible) | 0.00331% | 30,205 |
| European (non-Finnish) | 0.00138% | 72,671 |

*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 **375** 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.Phe375= 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 2023-12-11.

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

**Submission history:** 2 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-01-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-11 |

**Reported phenotype names (ClinVar):** not provided, CIT-related disorder, CIT-related condition, none provided.

## Same-residue context {#hotspot}

Residue **375** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CIT p.Phe375fs](/variant/cit-p-phe375fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CIT variant pages (same residue, condition, or type): [CIT p.Phe375fs](/variant/cit-p-phe375fs), [CIT p.Arg1178Ter](/variant/cit-p-arg1178ter), [CIT p.Arg220Ter](/variant/cit-p-arg220ter), [CIT c.4168+5G>A](/variant/cit-c-4168-plus-5g-a), [CIT p.Ala1144Thr](/variant/cit-p-ala1144thr), [CIT p.Ala1466Asp](/variant/cit-p-ala1466asp), [CIT p.Ala1527Val](/variant/cit-p-ala1527val), [CIT p.Ala244Val](/variant/cit-p-ala244val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2173063). 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.*