Is TBL2 p.Pro341Arg (c.1022C>G) pathogenic?

TBL2 p.Pro341Arg (c.1022C>G) is classified Uncertain significance in TBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: ambiguous (0.4853); Very rare (popmax 0.00305%, nfe).

How common is TBL2 p.Pro341Arg (c.1022C>G) in the general population?

TBL2 p.Pro341Arg (c.1022C>G) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about TBL2 p.Pro341Arg (c.1022C>G)?

AlphaMissense predicts ambiguous (score 0.4853) — an in-silico prediction, not a clinical call.

TBL2 p.Pro341Arg

c.1022C>G · VCV3324795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4853	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -9.47	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,039 bp · p 0.00087 · regional, not allelic
Overall
CADD	24.9	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 0.00305% European (non-Finnish) · 36/1,180,052 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00235% 38/1,613,820 alleles · very rare exomes 35/1,461,552 · genomes 3/152,268 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,779
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,094

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.Pro341Arg
Coding: c.1022C>G
MANE Select: NM_012453
Type: single nucleotide variant
Location: chr7:73570829 (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.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
TBL2 p.Ala139Val 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-pro341arg (accessed [today's date]).

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