# NM_014633.5(CTR9):c.594G>A (p.Ala198=)

https://sugi.bio/variant/ctr9-p-ala198

## Summary

**CTR9 p.Ala198= (c.594G>A)** is classified **Uncertain significance** in CTR9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). Ultra-rare (popmax 0.0368%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs754545267 · 3 submitters · ultra-rare (popmax 0.0368%, amr)

## 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 3 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 | [CTR9](https://sugi.bio/atlas/gene/CTR9/) |
| Protein change (HGVS p.) | p.Ala198= |
| Coding change (HGVS c.) | c.594G>A |
| MANE Select transcript | [NM_014633](https://www.ncbi.nlm.nih.gov/nuccore/NM_014633) |
| dbSNP | [rs754545267](https://www.ncbi.nlm.nih.gov/snp/rs754545267/) |
| Variant type | single nucleotide variant |
| Location | chr11:10760174-10760174 (GRCh38) |
| ClinVar | [VCV1430954](https://www.ncbi.nlm.nih.gov/clinvar/variation/1430954/) |

**All HGVS expressions:** `NC_000011.10:g.10760174G>A`, `NC_000011.9:g.10781721G>A`, `NG_051671.1:g.14188G>A`, `NM_001346279.2:c.594G>A`, `NM_014633.4:c.594G>A`, `NM_014633.5:c.594G>A`

## 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 gain** (Δ 0.85) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.486, GERP -1.94, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 22.6**. 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 **0.04**, donor loss **0.00**, acceptor gain **0.85**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.85**, donor gain **0.00**.
- Pangolin: Δ**0.59** (gain), gain 0.59 / loss 0.14. Agrees with SpliceAI. 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 **0.0368%** (amr) · FAF95 0.0249% · FAF99 0.0209% · 22/59,842 in the highest group · 79/1,612,574 alleles overall — ultra-rare (popmax 0.0368%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0368% | 2,720 |
| Middle Eastern | 0.0165% | 6,078 |
| South Asian | 0.011% | 9,089 |
| European (non-Finnish) | 0.00373% | 26,798 |
| African / African-American | 0.00267% | 37,427 |

*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 **198** 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-08.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-07-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-08 |

**Reported phenotype names (ClinVar):** not provided, CTR9-related disorder, CTR9-related condition, none provided.

## Similar variants {#similar}

Related CTR9 variant pages (same residue, condition, or type): [CTR9 p.Ala198fs](/variant/ctr9-p-ala198fs), [CTR9 p.Asn455Ser](/variant/ctr9-p-asn455ser), [CTR9 p.Ile17Thr](/variant/ctr9-p-ile17thr), [CTR9 p.Pro25Arg](/variant/ctr9-p-pro25arg), [CTR9 c.1960+3G>A](/variant/ctr9-c-1960-plus-3g-a), [CTR9 c.2109+4A>G](/variant/ctr9-c-2109-plus-4a-g), [CTR9 c.2445-3T>C](/variant/ctr9-c-2445-minus-3t-c), [CTR9 c.45+5G>T](/variant/ctr9-c-45-plus-5g-t).

### 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 1430954). 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.*