Is CBS p.Ala114= (c.342G>A) pathogenic?

CBS p.Ala114= (c.342G>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0103%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with CBS p.Ala114= (c.342G>A)?

CBS p.Ala114= (c.342G>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Ala114= (c.342G>A) in the general population?

CBS p.Ala114= (c.342G>A) is ultra-rare (popmax 0.0103%, eas) (gnomAD).

CBS p.Ala114=

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.342G>A · rs145338910 · VCV263580

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, eas)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.74	acceptor gain · deltas
Pangolin	Δ0.47	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -1	GERP 0.37, phastCons 0.001
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% East Asian · 4/38,686 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00212%

Overall 0.00319% 26/815,450 alleles · ultra-rare exomes 23/755,832 · genomes 3/59,618 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0103%	9,671
Admixed American	0.00876%	11,418
African / African-American	0.00453%	22,058
European (non-Finnish)	0.00313%	31,969

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: CBS
Protein: p.Ala114=
Coding: c.342G>A
MANE Select: NM_000071
dbSNP: rs145338910
Type: single nucleotide variant
Location: chr21:43066352 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 114: a β-strand; a UniProt-annotated variant site (in cbsd; mild form; when linked with w-58 severe form; decreased cystathionine beta-synthase activity; decreases homotetramer formation by promoting formation of larger aggregates)

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS p.Ala114Val Pathogenic/Likely pathogenic ★★ ⚠ same residue
CBS p.Ala114Ser Likely pathogenic ★ ⚠ same residue
CBS p.Ala114Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala288Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala331Glu Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg121His Pathogenic/Likely pathogenic ★★ 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/cbs-p-ala114 (accessed [today's date]).

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