# NM_014633.5(CTR9):c.598G>A (p.Val200Ile)

https://sugi.bio/variant/ctr9-p-val200ile

## Summary

**CTR9 p.Val200Ile (c.598G>A)** is classified **Uncertain significance** in CTR9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-08). AlphaMissense: likely benign (0.2935); Absent from gnomAD v4.1; Associated with Predisposition to Wilms tumor.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTR9 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Predisposition to Wilms tumor.

*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 | [CTR9](https://sugi.bio/atlas/gene/CTR9/) |
| Protein change (HGVS p.) | p.Val200Ile |
| Coding change (HGVS c.) | c.598G>A |
| MANE Select transcript | [NM_014633](https://www.ncbi.nlm.nih.gov/nuccore/NM_014633) |
| Variant type | single nucleotide variant |
| Location | chr11:10760178-10760178 (GRCh38) |
| ClinVar | [VCV3602717](https://www.ncbi.nlm.nih.gov/clinvar/variation/3602717/) |

**All HGVS expressions:** `NC_000011.10:g.10760178G>A`, `NC_000011.9:g.10781725G>A`, `NG_051671.1:g.14192G>A`, `NM_001346279.2:c.598G>A`, `NM_014633.5:c.598G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2935)
- REVEL 0.322 (indeterminate)
- SaProt LLR -8.41 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.55) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.916, GERP 2.2, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.4**. 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 0.74** across the covering region of the MANE Select transcript (10,755,712–10,761,998), spanning 6,286 bp. Chi-square p 0.0012. 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 **0.55**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.55**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CTR9** population constraint: LOEUF 0.368, pLI 1, missense-Z 4.7753. *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):

- **CTR9-related neurodevelopmental disorder** — Moderate (AD)

## Protein context {#protein}

Residue **200** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 76.62, 43% of residues very-high.

**21 experimental structure(s)** (PDB): [5ZYQ](https://www.rcsb.org/structure/5ZYQ), [6GMH](https://www.rcsb.org/structure/6GMH), [6TED](https://www.rcsb.org/structure/6TED), [7OOP](https://www.rcsb.org/structure/7OOP), [7OPC](https://www.rcsb.org/structure/7OPC), [7OPD](https://www.rcsb.org/structure/7OPD).

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

*Describes the biological roles of CTR9 (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:** CTR9 participates in disease-associated pathways. In Reactome, CTR9 is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** CTR9 loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588).

### Pathways affected {#pathways}

CTR9 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| [CHD1 and CHD2 subfamily](https://reactome.org/content/detail/R-HSA-9943411) | curated |
| [E3 ubiquitin ligases ubiquitinate target proteins](https://reactome.org/content/detail/R-HSA-8866654) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Biological process:** transcription elongation by RNA polymerase II, stem cell population maintenance, negative regulation of myeloid cell differentiation, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-08 |

## Associated conditions {#conditions}

[Predisposition to Wilms tumor](https://sugi.bio/atlas/disease/predisposition-to-wilms-tumor/).

**Reported phenotype names (ClinVar):** Predisposition to Wilms tumor.

## Similar variants {#similar}

Related CTR9 variant pages (same residue, condition, or type): [CTR9 p.Val200Ala](/variant/ctr9-p-val200ala), [CTR9 c.1960+3G>A](/variant/ctr9-c-1960-plus-3g-a), [CTR9 c.45+5G>T](/variant/ctr9-c-45-plus-5g-t), [CTR9 p.Ala370Thr](/variant/ctr9-p-ala370thr), [CTR9 p.Ala567Ser](/variant/ctr9-p-ala567ser), [CTR9 p.Arg1095Lys](/variant/ctr9-p-arg1095lys), [CTR9 p.Arg1122His](/variant/ctr9-p-arg1122his), [CTR9 p.Lys282Arg](/variant/ctr9-p-lys282arg).

### 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 3602717). 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.*