Is TBCD p.Ser956Phe (c.2867C>T) pathogenic?

TBCD p.Ser956Phe (c.2867C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-11). AlphaMissense: likely benign (0.1247); Ultra-rare (popmax 0.0264%, sas); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ser956Phe (c.2867C>T)?

TBCD p.Ser956Phe (c.2867C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ser956Phe (c.2867C>T) in the general population?

TBCD p.Ser956Phe (c.2867C>T) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about TBCD p.Ser956Phe (c.2867C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

TBCD p.Ser956Phe

c.2867C>T · rs567316358 · VCV1302399

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.3, phastCons 0.071
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0264% South Asian · 24/91,074 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00304% 49/1,613,102 alleles · ultra-rare exomes 44/1,460,752 · genomes 5/152,350 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,795
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00186%	53,622

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.Ser956Phe
Coding: c.2867C>T
MANE Select: NM_005993
dbSNP: rs567316358
Type: single nucleotide variant
Location: chr17:82929376 (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.Ser956= 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-ser956phe (accessed [today's date]).

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