Is TBL2 p.Arg427Ser (c.1281G>C) pathogenic?

TBL2 p.Arg427Ser (c.1281G>C) is classified Uncertain significance in TBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely pathogenic (0.9163); Very rare (popmax 0.00169%, amr).

How common is TBL2 p.Arg427Ser (c.1281G>C) in the general population?

TBL2 p.Arg427Ser (c.1281G>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about TBL2 p.Arg427Ser (c.1281G>C)?

AlphaMissense predicts likely pathogenic (score 0.9163) — an in-silico prediction, not a clinical call.

TBL2 p.Arg427Ser

c.1281G>C · rs529493631 · VCV3174826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9163	likely pathogenic
REVEL	0.18	moderately benign-leaning
SaProt	LLR -13.41	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,039 bp · p 0.00087 · regional, not allelic
Overall
CADD	25.1	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 0.00169% Admixed American · 1/59,104 alleles

Overall 6.22e-05% 1/1,608,590 alleles · very rare exomes 0/1,456,272 · genomes 1/152,318 · 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: TBL2
Protein: p.Arg427Ser
Coding: c.1281G>C
MANE Select: NM_012453
dbSNP: rs529493631
Type: single nucleotide variant
Location: chr7:73570570 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.11

Full TBL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TBL2 p.Arg427Met Uncertain significance ★ ⚠ same residue
TBL2 p.Ala189= Benign/Likely benign ★★ same type
TBL2 p.Ala332= Benign/Likely benign ★★ same type
TBL2 p.Gln229= Benign ★★ same type
TBL2 p.Glu135= Benign ★★ same type
TBL2 p.Glu257Ala Benign ★★ same type
TBL2 c.599-7C>A Uncertain significance ★ same type
TBL2 p.Ala139Thr 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/tbl2-p-arg427ser (accessed [today's date]).

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