# NM_001012759.3(CTU2):c.474G>A (p.Ser158=)

https://sugi.bio/variant/ctu2-p-ser158

## Summary

**CTU2 p.Ser158= (c.474G>A)** is classified **Likely benign** in CTU2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0365%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs759082825 · 3 submitters · ultra-rare (popmax 0.0365%, nfe)

## For patients & families {#patients}

This is a change in the CTU2 gene that is classified as likely benign — not considered disease-causing, 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 | [CTU2](https://sugi.bio/atlas/gene/CTU2/) |
| Protein change (HGVS p.) | p.Ser158= |
| Coding change (HGVS c.) | c.474G>A |
| MANE Select transcript | [NM_001012759](https://www.ncbi.nlm.nih.gov/nuccore/NM_001012759) |
| dbSNP | [rs759082825](https://www.ncbi.nlm.nih.gov/snp/rs759082825/) |
| Variant type | single nucleotide variant |
| Location | chr16:88712642-88712642 (GRCh38) |
| ClinVar | [VCV2055160](https://www.ncbi.nlm.nih.gov/clinvar/variation/2055160/) |

**All HGVS expressions:** `NC_000016.10:g.88712642G>A`, `NC_000016.9:g.88779050G>A`, `NM_001012759.2:c.474G>A`, `NM_001012759.3:c.474G>A`, `NM_001012762.3:c.474G>A`, `NM_001318507.2:c.687G>A`, `NM_001318513.2:c.213G>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 (below), not from a missing predictor score.
- Conservation: phyloP -20, GERP -4.26 — fast-evolving / accelerated position
- CADD: **PHRED 0.005**. 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 (G>T, Δ0.34 acceptor gain), 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 (gnomAD v4.1): grpmax **0.0365%** (nfe) · FAF95 0.0337% · FAF99 0.0325% · 431/1,179,472 in the highest group · 454/1,610,286 alleles overall — ultra-rare (popmax 0.0365%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0365% | 2,737 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,898 |
| Finnish (not grpmax-eligible) | 0.00956% | 10,465 |
| South Asian | 0.0066% | 15,154 |
| African / African-American | 0.00534% | 18,738 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-27 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |

**Reported phenotype names (ClinVar):** not provided, CTU2-related disorder, none provided, CTU2-related condition.

## Similar variants {#similar}

Related CTU2 variant pages (same residue, condition, or type): [CTU2 p.Ser158Leu](/variant/ctu2-p-ser158leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2055160). 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.*