Is TAB1 p.Arg489Cys (c.1465C>T) pathogenic?

TAB1 p.Arg489Cys (c.1465C>T) is classified Uncertain significance in TAB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely benign (0.2152); Ultra-rare (popmax 0.0493%, mid).

How common is TAB1 p.Arg489Cys (c.1465C>T) in the general population?

TAB1 p.Arg489Cys (c.1465C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about TAB1 p.Arg489Cys (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.2152) — an in-silico prediction, not a clinical call.

TAB1 p.Arg489Cys

c.1465C>T · rs747562603 · VCV2354615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2152	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -12.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 30 kb · p 0.0045 · regional, not allelic
Overall
CADD	34.0	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.013% 210/1,613,686 alleles · ultra-rare exomes 193/1,461,460 · genomes 17/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0362%	2,760
Admixed American	0.025%	4,001
European (non-Finnish)	0.0122%	8,195
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.00934%	10,706
East Asian	0.00223%	44,896

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: TAB1
Protein: p.Arg489Cys
Coding: c.1465C>T
MANE Select: NM_006116
dbSNP: rs747562603
Type: single nucleotide variant
Location: chr22:39430172 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.82 · 35 PDB
Residue 489: an α-helix

Full TAB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TAB1 p.Arg489His Uncertain significance ★ ⚠ same residue
TAB1 c.325-5C>T Benign ★★ same type
TAB1 p.His355= Benign ★★ same type
TAB1 p.Ala171Val Uncertain significance ★ ⚠ same type
TAB1 p.Ala225Ser Uncertain significance ★ ⚠ same type
TAB1 p.Ala260Val Uncertain significance ★ ⚠ same type
TAB1 p.Ala325Thr Uncertain significance ★ ⚠ same type
TAB1 p.Ala397Thr 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/tab1-p-arg489cys (accessed [today's date]).

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