Is TUBB2B p.Leu289Phe (c.865C>T) pathogenic?

TUBB2B p.Leu289Phe (c.865C>T) is classified Likely pathogenic in TUBB2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.9905); Absent from gnomAD v4.1; Associated with TUBB2B-related disorder.

What condition is associated with TUBB2B p.Leu289Phe (c.865C>T)?

TUBB2B p.Leu289Phe (c.865C>T) is associated with TUBB2B-related disorder (ClinVar).

How common is TUBB2B p.Leu289Phe (c.865C>T) in the general population?

TUBB2B p.Leu289Phe (c.865C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TUBB2B p.Leu289Phe (c.865C>T)?

AlphaMissense predicts likely pathogenic (score 0.9905) — an in-silico prediction, not a clinical call.

TUBB2B p.Leu289Phe

c.865C>T · VCV4973546

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9905 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TUBB2B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9905	likely pathogenic ✓ concordant with ClinVar
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.02	constrained · MANE · 711 bp · p 5.1e-69 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TUBB2B
Protein: p.Leu289Phe
Coding: c.865C>T
MANE Select: NM_178012
Type: single nucleotide variant
Location: chr6:3225224 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 3 PDB

Full TUBB2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TUBB2B-related disorder

Similar variants

TUBB2B p.Arg2His Likely pathogenic ★★ same condition
TUBB2B p.Arg380His Pathogenic/Likely pathogenic ★★ same condition
TUBB2B p.Gln11Leu Likely pathogenic ★★ same condition
TUBB2B p.Ala97Ser Likely pathogenic ★ same condition
TUBB2B p.Gln11Arg Likely pathogenic ★ same condition
TUBB2B p.Asp431Glu Uncertain significance ★ ⚠ same condition
TUBB2B p.Gln291Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
TUBB2B p.Gly98Arg Conflicting classifications of pathogenicity ★ ⚠ 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/tubb2b-p-leu289phe (accessed [today's date]).

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