# NM_006079.5(CITED2):c.388C>G (p.Pro130Ala)

https://sugi.bio/variant/cited2-p-pro130ala

## Summary

**CITED2 p.Pro130Ala (c.388C>G)** is classified **Uncertain significance** in CITED2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-21). AlphaMissense: likely benign (0.2497); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CITED2 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 | [CITED2](https://sugi.bio/atlas/gene/CITED2/) |
| Protein change (HGVS p.) | p.Pro130Ala |
| Coding change (HGVS c.) | c.388C>G |
| MANE Select transcript | [NM_006079](https://www.ncbi.nlm.nih.gov/nuccore/NM_006079) |
| Variant type | single nucleotide variant |
| Location | chr6:139373557-139373557 (GRCh38) |
| ClinVar | [VCV4003152](https://www.ncbi.nlm.nih.gov/clinvar/variation/4003152/) |

**All HGVS expressions:** `NC_000006.11:g.139694694G>C`, `NC_000006.12:g.139373557G>C`, `NG_016169.1:g.6092C>G`, `NM_001168388.3:c.388C>G`, `NM_001168389.3:c.403C>G`, `NM_006079.5:c.388C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2497)
- REVEL 0.426 (indeterminate)
- SaProt LLR -6.546 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.401, GERP 0.868, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.7**. 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 1.22** across the covering region of the MANE Select transcript (139,373,285–139,373,944), spanning 659 bp. Chi-square p 8.7e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000365% · FAF99 0.000137% · 1/6,062 in the highest group · 5/1,461,834 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| South Asian | 0.0022% | 45,539 |
| European (non-Finnish) | 0.000169% | 590,002 |

*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}

**CITED2** population constraint: LOEUF 0.588, pLI 0.89808, missense-Z -1.0202; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **congenital heart disease** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 52.07, 0% of residues very-high.

**4 experimental structure(s)** (PDB): [1P4Q](https://www.rcsb.org/structure/1P4Q), [1R8U](https://www.rcsb.org/structure/1R8U), [7LVS](https://www.rcsb.org/structure/7LVS), [7QGS](https://www.rcsb.org/structure/7QGS).

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

*Describes the biological roles of CITED2 (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:** CITED2's established molecular role includes transcription coactivator activity.


### Pathways affected {#pathways}

CITED2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of the TFAP2 (AP-2) family of transcription factors](https://reactome.org/content/detail/R-HSA-8866907) | curated |
| [FOXO-mediated transcription of cell death genes](https://reactome.org/content/detail/R-HSA-9614657) | curated |
| [Regulation of gene expression by Hypoxia-inducible Factor](https://reactome.org/content/detail/R-HSA-1234158) | curated |
| [TFAP2 (AP-2) family regulates transcription of other transcription factors](https://reactome.org/content/detail/R-HSA-8866906) | curated |

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

**Molecular function:** transcription coactivator activity, transcription corepressor activity, protein domain specific binding, histone acetyltransferase binding, LBD domain binding, molecular function activator activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, response to hypoxia, heart development, cell population proliferation, positive regulation of gene expression, negative regulation of gene expression.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-21.

**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 | 2025-04-21 |

## 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 CITED2 variant pages (same residue, condition, or type): [CITED2 p.Pro130Arg](/variant/cited2-p-pro130arg), [CITED2 p.Pro130Ser](/variant/cited2-p-pro130ser), [CITED2 p.Ala25Pro](/variant/cited2-p-ala25pro), [CITED2 p.Ala25Val](/variant/cited2-p-ala25val), [CITED2 p.Pro128Ser](/variant/cited2-p-pro128ser), [CITED2 p.Ala203Val](/variant/cited2-p-ala203val), [CITED2 p.Ala206Val](/variant/cited2-p-ala206val), [CITED2 p.Ala211Thr](/variant/cited2-p-ala211thr).

### 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 4003152). 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.*