Is TUBA4A p.Pro173Arg (c.518C>G) pathogenic?

TUBA4A p.Pro173Arg (c.518C>G) is classified Pathogenic in TUBA4A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with spastic ataxia 11, autosomal dominant.

What condition is associated with TUBA4A p.Pro173Arg (c.518C>G)?

TUBA4A p.Pro173Arg (c.518C>G) is associated with spastic ataxia 11, autosomal dominant (ClinVar).

How common is TUBA4A p.Pro173Arg (c.518C>G) in the general population?

TUBA4A p.Pro173Arg (c.518C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TUBA4A p.Pro173Arg (c.518C>G)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

TUBA4A p.Pro173Arg

c.518C>G · VCV3901250

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spastic ataxia 11, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic ✓ concordant with ClinVar
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -15.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 683 bp · p 1.6e-28 · regional, not allelic
Overall
CADD	28.4	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: TUBA4A
Protein: p.Pro173Arg
Coding: c.518C>G
MANE Select: NM_006000
Type: single nucleotide variant
Location: chr2:219251181 (GRCh38)
Gene constraint: LOEUF 0.945 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.02
Residue 173: a UniProt-annotated variant site (in spax11; likely pathogenic; altered tuba4a incorporation into microtubules and microtubules organization)

Full TUBA4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spastic ataxia 11, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TUBA4A p.Pro173Ser Pathogenic same residue
TUBA4A p.Arg105Cys Likely pathogenic ★★ same condition
TUBA4A p.Ser178Phe Likely pathogenic ★ same condition
TUBA4A p.Arg320Cys Likely pathogenic ★★ same type
TUBA4A p.Leu227Phe Pathogenic ★★ same type
TUBA4A c.227-74C>A Benign ★★ same type
TUBA4A c.3+47C>G Benign ★★ same type
TUBA4A c.3+98T>C Likely benign ★★ 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/tuba4a-p-pro173arg (accessed [today's date]).

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