# NM_001012759.3(CTU2):c.678C>T (p.Ser226=)

https://sugi.bio/variant/ctu2-p-ser226

## Summary

**CTU2 p.Ser226= (c.678C>T)** is classified **Likely benign** in CTU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTU2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [CTU2](https://sugi.bio/atlas/gene/CTU2/) |
| Protein change (HGVS p.) | p.Ser226= |
| Coding change (HGVS c.) | c.678C>T |
| MANE Select transcript | [NM_001012759](https://www.ncbi.nlm.nih.gov/nuccore/NM_001012759) |
| Variant type | single nucleotide variant |
| Location | chr16:88712846-88712846 (GRCh38) |
| ClinVar | [VCV4823243](https://www.ncbi.nlm.nih.gov/clinvar/variation/4823243/) |

**All HGVS expressions:** `NC_000016.10:g.88712846C>T`, `NC_000016.9:g.88779254C>T`, `NM_001012759.3:c.678C>T`, `NM_001012762.3:c.678C>T`, `NM_001318507.2:c.891C>T`, `NM_001318513.2:c.417C>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 (below), not from a missing predictor score.
- Conservation: phyloP 1.112, GERP -1.66, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 6.812**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.29 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**CTU2** population constraint: LOEUF 1.535, pLI 5.4023e-34, missense-Z -5.9994. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.27, 59% of residues very-high.

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

*Describes the biological roles of CTU2 (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.*


### Pathways affected {#pathways}

CTU2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [tRNA modification in the nucleus and cytosol](https://reactome.org/content/detail/R-HSA-6782315) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CTU2 variant pages (same residue, condition, or type): [CTU2 c.1420-1G>A](/variant/ctu2-c-1420-minus-1g-a), [CTU2 c.282+5G>A](/variant/ctu2-c-282-plus-5g-a), [CTU2 p.Gln243Ter](/variant/ctu2-p-gln243ter), [CTU2 p.Thr291=](/variant/ctu2-p-thr291), [CTU2 p.Ala176Val](/variant/ctu2-p-ala176val), [CTU2 p.Ala400Thr](/variant/ctu2-p-ala400thr), [CTU2 p.Arg270Cys](/variant/ctu2-p-arg270cys), [CTU2 p.Arg443Cys](/variant/ctu2-p-arg443cys).

### 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 4823243). 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.*