Is CBS p.Asn228Ser (c.683A>G) pathogenic?

CBS p.Asn228Ser (c.683A>G) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-15). AlphaMissense: ambiguous (0.4678); Absent from gnomAD v4.1; Associated with homocystinuria.

What condition is associated with CBS p.Asn228Ser (c.683A>G)?

CBS p.Asn228Ser (c.683A>G) is associated with homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Asn228Ser (c.683A>G) in the general population?

CBS p.Asn228Ser (c.683A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Asn228Ser (c.683A>G)?

AlphaMissense predicts ambiguous (score 0.4678) — an in-silico prediction, not a clinical call.

CBS p.Asn228Ser

c.683A>G · rs1555874803 · VCV553698

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4678 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

homocystinuria

Computational evidence

Protein change
AlphaMissense	0.4678	ambiguous
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -11.44	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 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	26.7	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.Asn228Ser
Coding: c.683A>G
MANE Select: NM_000071
dbSNP: rs1555874803
Type: single nucleotide variant
Location: chr21:43065256 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 228: an α-helix; a UniProt-annotated variant site (in cbsd; loss of cystathionine beta-synthase activity; decreased homotetramer formation); a UniProt-annotated variant site (in cbsd; has significantly decreased levels of enzyme activity)

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

Disease context

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

Also linked: classic homocystinuria

Similar variants

CBS p.Asn228Lys Pathogenic ★★ same residue
CBS p.Asn228= 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-asn228ser (accessed [today's date]).

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