Is CBS p.Ala331Glu (c.992C>A) pathogenic?

CBS p.Ala331Glu (c.992C>A) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-07-17). AlphaMissense: likely pathogenic (0.858); Absent from gnomAD v4.1; Associated with CBS-related disorder.

What condition is associated with CBS p.Ala331Glu (c.992C>A)?

CBS p.Ala331Glu (c.992C>A) is associated with CBS-related disorder, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Ala331Glu (c.992C>A) in the general population?

CBS p.Ala331Glu (c.992C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala331Glu (c.992C>A)?

AlphaMissense predicts likely pathogenic (score 0.858) — an in-silico prediction, not a clinical call.

CBS p.Ala331Glu

c.992C>A · rs777919630 · VCV212857

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.858 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 2,712)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBS-related disorder

Computational evidence

Protein change
AlphaMissense	0.858	likely pathogenic ✓ concordant with ClinVar
REVEL	0.712	pathogenic-leaning
SaProt	LLR -13.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	25.0	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

No allele count reported in gnomAD v4.1 (AN 2,712). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CBS
Protein: p.Ala331Glu
Coding: c.992C>A
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

CBS-related disorder

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

Similar variants

CBS p.Ala331= Likely benign ★★ same residue
CBS p.Ala331Val 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
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-ala331glu (accessed [today's date]).

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