Is BUB1 p.Met1Arg (c.2T>G) pathogenic?

BUB1 p.Met1Arg (c.2T>G) is classified Uncertain significance in BUB1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-10). Very rare (popmax 0.00161%, nfe); Associated with microcephaly 30, primary, autosomal recessive.

What condition is associated with BUB1 p.Met1Arg (c.2T>G)?

BUB1 p.Met1Arg (c.2T>G) is associated with microcephaly 30, primary, autosomal recessive (ClinVar).

How common is BUB1 p.Met1Arg (c.2T>G) in the general population?

BUB1 p.Met1Arg (c.2T>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

BUB1 p.Met1Arg

c.2T>G · rs778053608 · VCV1806481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

microcephaly 30, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.31	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,177,726 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00118% 19/1,607,980 alleles · very rare

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: BUB1
Protein: p.Met1Arg
Coding: c.2T>G
MANE Select: NM_004336
dbSNP: rs778053608
Type: single nucleotide variant
Location: chr2:110677994 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 1: the 'necessary for kinetochore localization' region

Full BUB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 30, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BUB1 p.Ile103Phe Uncertain significance ★ ⚠ same condition
BUB1 c.2625+1G>A Pathogenic same condition
BUB1 p.Pro478fs Likely pathogenic ★ same condition
BUB1 p.Ala733fs Pathogenic same condition
BUB1 c.1698+1G>T Uncertain significance ★★ same type
BUB1 p.Ala281Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala283Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala499Val 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/bub1-p-met1arg (accessed [today's date]).

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