# NM_003193.5(TBCE):c.181T>A (p.Cys61Ser)

https://sugi.bio/variant/tbce-p-cys61ser

## Summary

**TBCE p.Cys61Ser (c.181T>A)** is classified **Uncertain significance** in TBCE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.7075); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0134%, eas)

## For patients & families {#patients}

This is a change in the TBCE 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 | [TBCE](https://sugi.bio/atlas/gene/TBCE/) |
| Protein change (HGVS p.) | p.Cys61Ser |
| Coding change (HGVS c.) | c.181T>A |
| MANE Select transcript | [NM_003193](https://www.ncbi.nlm.nih.gov/nuccore/NM_003193) |
| Variant type | single nucleotide variant |
| Location | chr1:235401583-235401583 (GRCh38) |
| ClinVar | [VCV3966123](https://www.ncbi.nlm.nih.gov/clinvar/variation/3966123/) |

**All HGVS expressions:** `NC_000001.10:g.235564898T>A`, `NC_000001.11:g.235401583T>A`, `NG_009230.1:g.39171T>A`, `NG_009230.2:g.39158T>A`, `NM_001079515.3:c.181T>A`, `NM_001287801.2:c.181T>A`, `NM_001287802.2:c.-210-12850T>A`, `NM_003193.5:c.181T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7075)
- REVEL 0.791 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -5.534 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.641, GERP 1.43, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in TBCE (of 3,061 modeled).
- CADD: **PHRED 24.0**. 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 1.00** across the covering region of the MANE Select transcript (235,380,050–235,448,759), spanning 68,709 bp. Chi-square p 0.95. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.48 donor 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 **0.0134%** (eas) · FAF95 0.00579% · FAF99 0.00394% · 6/44,866 in the highest group · 7/1,613,258 alleles overall — ultra-rare (popmax 0.0134%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0134% | 7,478 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,458 |

*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}

**TBCE** population constraint: LOEUF 0.868, pLI 2.2119e-12, missense-Z 0.41471; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **encephalopathy, progressive, with amyotrophy and optic atrophy** — Moderate (AR)

## Protein context {#protein}

Residue **61** lies in the cap-gly domain.

AlphaFold model confidence (whole protein): pLDDT 89.27, 72% of residues very-high.

**6 experimental structure(s)** (PDB): [4ICU](https://www.rcsb.org/structure/4ICU), [4ICV](https://www.rcsb.org/structure/4ICV), [9M1J](https://www.rcsb.org/structure/9M1J), [9M1K](https://www.rcsb.org/structure/9M1K), [9M1L](https://www.rcsb.org/structure/9M1L), [9M1M](https://www.rcsb.org/structure/9M1M).

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

*Describes the biological roles of TBCE (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-chaperonin tubulin folding pathway](https://reactome.org/content/detail/R-HSA-389977) | electronic |

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

**Biological process:** microtubule cytoskeleton organization, post-chaperonin tubulin folding pathway, mitotic spindle organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-07.

**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 | 2025-06-07 |

## 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 TBCE variant pages (same residue, condition, or type): [B3GALNT2 p.Gly492Ser](/variant/b3galnt2-p-gly492ser), [TBCE c.738-3C>T](/variant/tbce-c-738-minus-3c-t), [TBCE c.898+5A>G](/variant/tbce-c-898-plus-5a-g), [TBCE p.Arg71His](/variant/tbce-p-arg71his), [TBCE p.Arg88Cys](/variant/tbce-p-arg88cys), [TBCE p.Asn87Thr](/variant/tbce-p-asn87thr), [TBCE p.Cys141Tyr](/variant/tbce-p-cys141tyr), [TBCE p.Glu376Asp](/variant/tbce-p-glu376asp).

### 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 3966123). 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.*