Is CBS p.Ala114Val (c.341C>T) pathogenic?

CBS p.Ala114Val (c.341C>T) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 24 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2866); Ultra-rare (popmax 0.0155%, eas); Associated with CBS-related disorder.

What condition is associated with CBS p.Ala114Val (c.341C>T)?

CBS p.Ala114Val (c.341C>T) is associated with CBS-related disorder, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Ala114Val (c.341C>T) in the general population?

CBS p.Ala114Val (c.341C>T) is ultra-rare (popmax 0.0155%, eas) (gnomAD).

What do computational predictors say about CBS p.Ala114Val (c.341C>T)?

AlphaMissense predicts likely benign (score 0.2866) — an in-silico prediction, not a clinical call.

CBS p.Ala114Val

c.341C>T · rs121964964 · VCV119

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 24 submitters

AlphaMissense

likely benign

0.2866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBS-related disorder

Computational evidence

Protein change
AlphaMissense	0.2866	likely benign ⚠ discordant with ClinVar
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -10.32	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	26.2	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 0.0155% East Asian · 6/38,706 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00972%

Overall 0.0107% 87/813,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0155%	6,451
Admixed American	0.0153%	6,521
European (non-Finnish)	0.0131%	7,630
Remaining individualsnot grpmax-eligible	0.00823%	12,145

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.Ala114Val
Coding: c.341C>T
MANE Select: NM_000071
dbSNP: rs121964964
Type: single nucleotide variant
Location: chr21:43066353 (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

CBS-related disorder

Also linked: homocystinuria classic homocystinuria familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Ala114= Conflicting classifications of pathogenicity ★ same residue
CBS p.Ala114Ser Likely pathogenic ★ ⚠ same residue
CBS p.Ala114Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.1358+1G>A Pathogenic ★★ same condition
CBS c.1359-1G>C 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-ala114val (accessed [today's date]).

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