Is TUBA3C p.Lys124Arg (c.371A>G) pathogenic?

TUBA3C p.Lys124Arg (c.371A>G) is classified Uncertain significance in TUBA3C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1124); Very rare (popmax 0.0011%, sas).

How common is TUBA3C p.Lys124Arg (c.371A>G) in the general population?

TUBA3C p.Lys124Arg (c.371A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TUBA3C p.Lys124Arg (c.371A>G)?

AlphaMissense predicts likely benign (score 0.1124) — an in-silico prediction, not a clinical call.

TUBA3C p.Lys124Arg

c.371A>G · VCV4193888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1124 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1124	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 7,881 bp · p 6.5e-18 · regional, not allelic
Overall
CADD	24.9	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 0.0011% South Asian · 1/91,058 alleles

Overall 6.2e-05% 1/1,614,134 alleles · very rare exomes 0/1,461,850 · genomes 1/152,284 · 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: TUBA3C
Protein: p.Lys124Arg
Coding: c.371A>G
MANE Select: NM_006001
Type: single nucleotide variant
Location: chr13:19178250 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.26

Full TUBA3C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TUBA3C p.Ala126Val Uncertain significance ★ ⚠ same type
TUBA3C p.Ala150Thr Uncertain significance ★ ⚠ same type
TUBA3C p.Ala330Val Uncertain significance ★ ⚠ same type
TUBA3C p.Ala403Thr Uncertain significance ★ ⚠ same type
TUBA3C p.Ala442Gly Uncertain significance ★ ⚠ same type
TUBA3C p.Arg121Gln Uncertain significance ★ same type
TUBA3C p.Arg121Trp Uncertain significance ★ ⚠ same type
TUBA3C p.Arg123Gly 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/tuba3c-p-lys124arg (accessed [today's date]).

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