Is CBS p.Ala355Pro (c.1063G>C) pathogenic?

CBS p.Ala355Pro (c.1063G>C) is classified Likely pathogenic in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.741); Absent from gnomAD v4.1; Associated with CBS-related disorder.

What condition is associated with CBS p.Ala355Pro (c.1063G>C)?

CBS p.Ala355Pro (c.1063G>C) is associated with CBS-related disorder, homocystinuria (ClinVar).

How common is CBS p.Ala355Pro (c.1063G>C) in the general population?

CBS p.Ala355Pro (c.1063G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala355Pro (c.1063G>C)?

AlphaMissense predicts likely pathogenic (score 0.741) — an in-silico prediction, not a clinical call.

CBS p.Ala355Pro

c.1063G>C · VCV3907322

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.741 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBS-related disorder

Computational evidence

Protein change
AlphaMissense	0.741	likely pathogenic ✓ concordant with ClinVar
REVEL	0.673	pathogenic-leaning
SaProt	LLR -16.24	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 0.4	GERP -2.2, phastCons 0.96
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	17.65	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.Ala355Pro
Coding: c.1063G>C
MANE Select: NM_000071
Type: single nucleotide variant
Location: chr21:43060523 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 355: 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

Similar variants

CBS p.Ala355= Conflicting classifications of pathogenicity ★ same residue
CBS p.Ala355Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.209+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.737-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBS c.828+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala114Val 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-ala355pro (accessed [today's date]).

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