Is TAB2 p.Cys684Arg (c.2050T>C) pathogenic?

TAB2 p.Cys684Arg (c.2050T>C) is classified Uncertain significance in TAB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with congenital heart defects, multiple types, 2.

What condition is associated with TAB2 p.Cys684Arg (c.2050T>C)?

TAB2 p.Cys684Arg (c.2050T>C) is associated with congenital heart defects, multiple types, 2 (ClinVar).

How common is TAB2 p.Cys684Arg (c.2050T>C) in the general population?

TAB2 p.Cys684Arg (c.2050T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TAB2 p.Cys684Arg (c.2050T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

TAB2 p.Cys684Arg

c.2050T>C · VCV3359038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital heart defects, multiple types, 2

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 1% in TAB2
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -14.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 12 kb · p 7.4e-11 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TAB2
Protein: p.Cys684Arg
Coding: c.2050T>C
MANE Select: NM_001292034
Type: single nucleotide variant
Location: chr6:149409687 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 53.24 · 6 PDB
Residue 684: the 'interaction with polyubiquitin' region

Full TAB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital heart defects, multiple types, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TAB2 p.Cys684Tyr Uncertain significance ★ ⚠ same residue
TAB2 p.Cys684Ser Uncertain significance ★ ⚠ same residue
TAB2 c.1764+1G>A Pathogenic/Likely pathogenic ★★ same condition
TAB2 p.Arg574Ter Likely pathogenic ★★ same condition
TAB2 p.Arg96Lys Uncertain significance ★★ ⚠ same condition
TAB2 p.His6Arg Uncertain significance ★★ ⚠ same condition
TAB2 p.Ile68Thr Uncertain significance ★★ same condition
TAB2 p.Ser50Asn 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/tab2-p-cys684arg (accessed [today's date]).

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