Is TUBB2A p.Pro243Arg (c.728C>G) pathogenic?

TUBB2A p.Pro243Arg (c.728C>G) is classified Uncertain significance in TUBB2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-15). AlphaMissense: likely pathogenic (0.988); Absent from gnomAD v4.1.

How common is TUBB2A p.Pro243Arg (c.728C>G) in the general population?

TUBB2A p.Pro243Arg (c.728C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TUBB2A p.Pro243Arg (c.728C>G)?

AlphaMissense predicts likely pathogenic (score 0.988) — an in-silico prediction, not a clinical call.

TUBB2A p.Pro243Arg

c.728C>G · rs1554122947 · VCV1998926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.988	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -17.12	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 9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.07	constrained · MANE · 790 bp · p 1.1e-67 · regional, not allelic
Overall
CADD	24.7	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

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: TUBB2A
Protein: p.Pro243Arg
Coding: c.728C>G
MANE Select: NM_001069
dbSNP: rs1554122947
Type: single nucleotide variant
Location: chr6:3154473 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 92.44 · 3 PDB

Full TUBB2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TUBB2A p.Pro243Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TUBB2A p.Pro243= Likely benign ★ same residue
TUBB p.Asn52Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
TUBB p.Asp327Asn Pathogenic/Likely pathogenic ★★ same type
TUBB p.Gln15His Likely pathogenic ★★ same type
TUBB p.Glu111Lys Pathogenic/Likely pathogenic ★★ same type
TUBB p.Glu401Lys Pathogenic ★★ same type
TUBB p.Met299Val Pathogenic ★★ 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/tubb2a-p-pro243arg (accessed [today's date]).

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