Is TRA2B p.Asp146Asn (c.436G>A) pathogenic?

TRA2B p.Asp146Asn (c.436G>A) is classified Uncertain significance in TRA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-14). AlphaMissense: ambiguous (0.4867); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRA2B p.Asp146Asn (c.436G>A)?

TRA2B p.Asp146Asn (c.436G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TRA2B p.Asp146Asn (c.436G>A) in the general population?

TRA2B p.Asp146Asn (c.436G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TRA2B p.Asp146Asn (c.436G>A)?

AlphaMissense predicts ambiguous (score 0.4867) — an in-silico prediction, not a clinical call.

TRA2B p.Asp146Asn

c.436G>A · VCV4839314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4867	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -8.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 4,333 bp · p 2.2e-28 · 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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,914 alleles · very rare exomes 5/1,461,792 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,446
European (non-Finnish)	0.000339%	294,998

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: TRA2B
Protein: p.Asp146Asn
Coding: c.436G>A
MANE Select: NM_004593
Type: single nucleotide variant
Location: chr3:185923882 (GRCh38)
Gene constraint: LOEUF 0.528 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 57.18 · 4 PDB
Residue 146: the rrm domain; a β-strand

Full TRA2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRA2B p.Ala17Pro Uncertain significance ★ ⚠ same condition
TRA2B p.Arg74His Uncertain significance ★ ⚠ same condition
TRA2B p.Arg82His Uncertain significance ★ ⚠ same condition
TRA2B p.Arg91Cys Uncertain significance ★ ⚠ same condition
TRA2B p.Asn8Thr Uncertain significance ★ ⚠ same condition
TRA2B p.Asp257Glu Uncertain significance ★ ⚠ same condition
TRA2B p.His98Arg Uncertain significance ★ ⚠ same condition
TRA2B p.Ser270Thr 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/tra2b-p-asp146asn (accessed [today's date]).

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