Is TBCB p.Ile34Val (c.100A>G) pathogenic?

TBCB p.Ile34Val (c.100A>G) is classified Uncertain significance in TBCB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0778); Very rare (popmax 0.0034%, sas).

How common is TBCB p.Ile34Val (c.100A>G) in the general population?

TBCB p.Ile34Val (c.100A>G) is very rare (popmax 0.0034%, sas) (gnomAD).

What do computational predictors say about TBCB p.Ile34Val (c.100A>G)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

TBCB p.Ile34Val

c.100A>G · VCV3804763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0034%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -0.16, phastCons 0.89
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.93 · regional, not allelic
Overall
CADD	19.37	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 0.0034% South Asian · 3/88,120 alleles

Filtering AF 0.000904% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000451%

Overall 0.000195% 3/1,540,682 alleles · very rare exomes 3/1,395,802 · genomes 0/144,880 · 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: TBCB
Protein: p.Ile34Val
Coding: c.100A>G
MANE Select: NM_001281
Type: single nucleotide variant
Location: chr19:36115660 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.55

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

Similar variants

TBCB p.Tyr197Asn Uncertain significance ★★ ⚠ same type
TBCB p.Ala218Gly Uncertain significance ★ ⚠ same type
TBCB p.Arg103Gly Uncertain significance ★ ⚠ same type
TBCB p.Arg103Pro Uncertain significance ★ ⚠ same type
TBCB p.Arg138Gln Uncertain significance ★ ⚠ same type
TBCB p.Arg148His Uncertain significance ★ ⚠ same type
TBCB p.Arg196Cys Uncertain significance ★ ⚠ same type
TBCB p.Arg212Cys Uncertain significance ★ ⚠ same type

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/tbcb-p-ile34val (accessed [today's date]).

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