Is TBCD p.Pro1183Ser (c.3547C>T) pathogenic?

TBCD p.Pro1183Ser (c.3547C>T) is classified Uncertain significance in TBCD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: ambiguous (0.5144); Ultra-rare (popmax 0.0827%, mid); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Pro1183Ser (c.3547C>T)?

TBCD p.Pro1183Ser (c.3547C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Pro1183Ser (c.3547C>T) in the general population?

TBCD p.Pro1183Ser (c.3547C>T) is ultra-rare (popmax 0.0827%, mid) (gnomAD).

What do computational predictors say about TBCD p.Pro1183Ser (c.3547C>T)?

AlphaMissense predicts ambiguous (score 0.5144) — an in-silico prediction, not a clinical call.

TBCD p.Pro1183Ser

c.3547C>T · VCV4632735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5144 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0827%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5144	ambiguous
REVEL	0.329	indeterminate
SaProt	LLR -12.95	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	24.7	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 0.0827% Middle Eastern · 5/6,044 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.000938% 15/1,599,888 alleles · ultra-rare exomes 15/1,447,538 · genomes 0/152,350 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0827%	1,209
South Asian	0.00452%	22,128
Remaining individualsnot grpmax-eligible	0.00161%	62,074
European (non-Finnish)	0.000426%	234,893

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.Pro1183Ser
Coding: c.3547C>T
MANE Select: NM_005993
Type: single nucleotide variant
Location: chr17:82941466 (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.Pro1183= Likely benign ★ 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
TBCD p.Ala599Thr Uncertain significance ★★ ⚠ same condition
TBCD p.Ala907Val 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-pro1183ser (accessed [today's date]).

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