# NM_005993.5(TBCD):c.513C>T (p.Asp171=)

https://sugi.bio/variant/tbcd-p-asp171

## Summary

**TBCD p.Asp171= (c.513C>T)** is classified **Likely benign** in TBCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). Ultra-rare (popmax 0.0117%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs753748524 · 2 submitters · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the TBCD gene that is classified as likely benign — not considered disease-causing, submitted by 2 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 | [TBCD](https://sugi.bio/atlas/gene/TBCD/) |
| Protein change (HGVS p.) | p.Asp171= |
| Coding change (HGVS c.) | c.513C>T |
| MANE Select transcript | [NM_005993](https://www.ncbi.nlm.nih.gov/nuccore/NM_005993) |
| dbSNP | [rs753748524](https://www.ncbi.nlm.nih.gov/snp/rs753748524/) |
| Variant type | single nucleotide variant |
| Location | chr17:82768497-82768497 (GRCh38) |
| ClinVar | [VCV2986722](https://www.ncbi.nlm.nih.gov/clinvar/variation/2986722/) |

**All HGVS expressions:** `NC_000017.10:g.80726373C>T`, `NC_000017.11:g.82768497C>T`, `NG_011721.1:g.21434C>T`, `NG_011721.2:g.21434C>T`, `NM_001411101.1:c.462C>T`, `NM_001411102.1:c.513C>T`, `NM_005993.5:c.513C>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 -5.655, GERP -4.59 — fast-evolving / accelerated position
- CADD: **PHRED 6.245**. 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>A, Δ0.22 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 **0.0117%** (amr) · FAF95 0.00544% · FAF99 0.00381% · 7/59,972 in the highest group · 80/1,613,628 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.219% | 456 |
| Finnish (not grpmax-eligible) | 0.0203% | 4,924 |
| Admixed American (grpmax) | 0.0117% | 8,567 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,617 |
| East Asian | 0.00446% | 22,441 |
| European (non-Finnish) | 0.00407% | 24,579 |
| South Asian | 0.0033% | 30,345 |
| African / African-American | 0.00134% | 74,860 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**TBCD** population constraint: LOEUF 0.763, pLI 2.6388e-20, missense-Z 0.89228. *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):

- **early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.45, 77% of residues very-high.

**6 experimental structure(s)** (PDB): [9M1I](https://www.rcsb.org/structure/9M1I), [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), [9M1N](https://www.rcsb.org/structure/9M1N).

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

*Describes the biological roles of TBCD (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:** TBCD's established molecular role includes GTPase activator activity.


### Pathways affected {#pathways}

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

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

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

**Molecular function:** GTPase activator activity, beta-tubulin binding.

**Biological process:** mitotic cell cycle, protein folding, tubulin complex assembly, post-chaperonin tubulin folding pathway, negative regulation of microtubule polymerization, cell morphogenesis involved in neuron differentiation.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-17.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-17 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-25 |

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

## Similar variants {#similar}

Related TBCD variant pages (same residue, condition, or type): [TBCD c.1224-2A>G](/variant/tbcd-c-1224-minus-2a-g), [TBCD c.2007-2A>G](/variant/tbcd-c-2007-minus-2a-g), [TBCD p.Ala475Thr](/variant/tbcd-p-ala475thr), [TBCD p.Ala554Val](/variant/tbcd-p-ala554val), [TBCD p.Arg113Ter](/variant/tbcd-p-arg113ter), [TBCD p.Arg303Ter](/variant/tbcd-p-arg303ter), [TBCD p.Arg323Ter](/variant/tbcd-p-arg323ter), [TBCD p.Arg436Ter](/variant/tbcd-p-arg436ter).

### 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 2986722). 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.*