Is TRA2B p.Ser266Phe (c.797C>T) pathogenic?

TRA2B p.Ser266Phe (c.797C>T) is classified Uncertain significance in TRA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely pathogenic (0.9923); Very rare (popmax 8.48e-05%, nfe).

How common is TRA2B p.Ser266Phe (c.797C>T) in the general population?

TRA2B p.Ser266Phe (c.797C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TRA2B p.Ser266Phe (c.797C>T)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

TRA2B p.Ser266Phe

c.797C>T · rs2473734969 · VCV2582209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -14.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 1,736 bp · p 0.015 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,358 alleles

Overall 6.2e-05% 1/1,613,208 alleles · very rare exomes 1/1,460,888 · genomes 0/152,320 · 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: TRA2B
Protein: p.Ser266Phe
Coding: c.797C>T
MANE Select: NM_004593
dbSNP: rs2473734969
Type: single nucleotide variant
Location: chr3:185918424 (GRCh38)
Gene constraint: LOEUF 0.528 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 57.18 · 4 PDB
Residue 266: the 'disordered' region

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

Similar variants

TRA2B c.170+1G>A Pathogenic ★ same type
TRA2B p.Gln7Ter Pathogenic ★ same type
TRA2B p.Thr201Met Pathogenic ★ same type
TRA2B c.171-2A>G Uncertain significance ★ same type
TRA2B c.782+5G>A Uncertain significance ★ same type
TRA2B p.Ala17Pro Uncertain significance ★ ⚠ same type
TRA2B p.Arg74His Uncertain significance ★ ⚠ same type
TRA2B p.Arg82His 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/tra2b-p-ser266phe (accessed [today's date]).

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