Is CBS p.Ala331Val (c.992C>T) pathogenic?

CBS p.Ala331Val (c.992C>T) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-09-16). AlphaMissense: ambiguous (0.3503); Absent from gnomAD v4.1; Associated with classic homocystinuria.

What condition is associated with CBS p.Ala331Val (c.992C>T)?

CBS p.Ala331Val (c.992C>T) is associated with classic homocystinuria, intellectual disability, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Ala331Val (c.992C>T) in the general population?

CBS p.Ala331Val (c.992C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala331Val (c.992C>T)?

AlphaMissense predicts ambiguous (score 0.3503) — an in-silico prediction, not a clinical call.

CBS p.Ala331Val

Q: How is Homocystinuria due to cystathionine beta-synthase deficiency inherited?

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

c.992C>T · rs777919630 · VCV193793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3503 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.3503	ambiguous
REVEL	0.701	pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	23.5	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: CBS
Protein: p.Ala331Val
Coding: c.992C>T
MANE Select: NM_000071
dbSNP: rs777919630
Type: single nucleotide variant
Location: chr21:43062358 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 331: an α-helix; a UniProt-annotated variant site (in cbsd)

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

Disease context

classic homocystinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability familial thoracic aortic aneurysm and aortic dissection

For Homocystinuria due to cystathionine beta-synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CBS p.Ala331Glu Pathogenic/Likely pathogenic ★★ same residue
CBS p.Ala331= Likely benign ★★ 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
CBS c.1468-1G>A 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-ala331val (accessed [today's date]).

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