Is TBCD p.Phe214Cys (c.641T>G) pathogenic?

TBCD p.Phe214Cys (c.641T>G) is classified Uncertain significance in TBCD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely pathogenic (0.7311); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Phe214Cys (c.641T>G)?

TBCD p.Phe214Cys (c.641T>G) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Phe214Cys (c.641T>G) in the general population?

TBCD p.Phe214Cys (c.641T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TBCD p.Phe214Cys (c.641T>G)?

AlphaMissense predicts likely pathogenic (score 0.7311) — an in-silico prediction, not a clinical call.

TBCD p.Phe214Cys

c.641T>G · VCV4632747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7311	likely pathogenic
REVEL	0.573	indeterminate
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,613,540 alleles · ultra-rare exomes 1/1,461,494 · genomes 0/152,046 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TBCD
Protein: p.Phe214Cys
Coding: c.641T>G
MANE Select: NM_005993
Type: single nucleotide variant
Location: chr17:82781591 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 6 PDB

Full TBCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tbcd-p-phe214cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown