Is TBCD p.Arg320Cys (c.958C>T) pathogenic?

TBCD p.Arg320Cys (c.958C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-05). AlphaMissense: ambiguous (0.5606); Very rare (popmax 0.0044%, sas); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Arg320Cys (c.958C>T)?

TBCD p.Arg320Cys (c.958C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Arg320Cys (c.958C>T) in the general population?

TBCD p.Arg320Cys (c.958C>T) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about TBCD p.Arg320Cys (c.958C>T)?

AlphaMissense predicts ambiguous (score 0.5606) — an in-silico prediction, not a clinical call.

TBCD p.Arg320Cys

c.958C>T · rs771304008 · VCV2161408

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5606	ambiguous
REVEL	0.369	indeterminate
SaProt	LLR -13.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	27.9	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 0.0044% South Asian · 4/90,970 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00112% 18/1,608,406 alleles · very rare exomes 17/1,456,226 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,743
Admixed American	0.00334%	29,958
Remaining individualsnot grpmax-eligible	0.00321%	31,113
East Asian	0.00224%	44,648
African / African-American	0.00134%	74,834
European (non-Finnish)	0.000681%	146,926

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.Arg320Cys
Coding: c.958C>T
MANE Select: NM_005993
dbSNP: rs771304008
Type: single nucleotide variant
Location: chr17:82805882 (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

Similar variants

TBCD p.Arg320His Uncertain significance ★ same residue
TBCD p.Arg320Ser Uncertain significance ★ ⚠ same residue
ZNF750 p.Gly320Arg Uncertain significance ★ ⚠ same residue
TBCD p.Gln330Ter Pathogenic ★★ same condition
TBCD p.Ala1159Val Uncertain significance ★★ ⚠ same condition
TBCD p.Ala1162Val Uncertain significance ★★ ⚠ same condition
TBCD p.Ala394Ser Uncertain significance ★★ ⚠ same condition
TBCD p.Ala415Val Uncertain significance ★★ ⚠ same condition

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-arg320cys (accessed [today's date]).

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