Is CBS p.Ala226Pro (c.676G>C) pathogenic?

CBS p.Ala226Pro (c.676G>C) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-12). AlphaMissense: likely benign (0.0804); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Ala226Pro (c.676G>C)?

CBS p.Ala226Pro (c.676G>C) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, classic homocystinuria (ClinVar).

How common is CBS p.Ala226Pro (c.676G>C) in the general population?

CBS p.Ala226Pro (c.676G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ala226Pro (c.676G>C)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

CBS p.Ala226Pro

c.676G>C · rs763835246 · VCV1310379

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR 0.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.99, phastCons 0.97
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	17.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Ala226Pro
Coding: c.676G>C
MANE Select: NM_000071
dbSNP: rs763835246
Type: single nucleotide variant
Location: chr21:43065263 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 226: a UniProt-annotated variant site (in cbsd; presents 20% of the wild-type activity; dramatically reduced capacity to form multimeric quaternary structure)

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

Disease context

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: classic homocystinuria

Similar variants

CBS p.Ala226Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
CBS p.Ala226Ser Likely pathogenic ★ ⚠ same residue
CBS p.Ala226Asp 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-ala226pro (accessed [today's date]).

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