Is CBS p.Ile278Ser (c.833T>G) pathogenic?

CBS p.Ile278Ser (c.833T>G) is classified Likely pathogenic in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-15). AlphaMissense: ambiguous (0.5552); Absent from gnomAD v4.1; Associated with classic homocystinuria.

What condition is associated with CBS p.Ile278Ser (c.833T>G)?

CBS p.Ile278Ser (c.833T>G) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Ile278Ser (c.833T>G) in the general population?

CBS p.Ile278Ser (c.833T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ile278Ser (c.833T>G)?

AlphaMissense predicts ambiguous (score 0.5552) — an in-silico prediction, not a clinical call.

CBS p.Ile278Ser

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.833T>G · rs5742905 · VCV3075863

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5552 · 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	0.5552	ambiguous
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -16.98	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.46	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	33.0	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

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.Ile278Ser
Coding: c.833T>G
MANE Select: NM_000071
dbSNP: rs5742905
Type: single nucleotide variant
Location: chr21:43063074 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 278: a β-strand; a UniProt-annotated variant site (in cbsd; loss of activity); a UniProt-annotated variant site (in cbsd; mild to severe form; common mutation; decreased expression; loss of cystathionine beta-synthase activity; impaired stimulation by adomet and adohcy; severely affects homotetramer formation by promoting formation of larger aggregates)

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

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.Ile278Thr Pathogenic ★★ ⚠ same residue
CBS p.Ile278delinsThrGlyValAspHisProGlyGlyAlaPheAlaGlyLeuGluProTer Likely pathogenic ★ 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-ile278ser (accessed [today's date]).

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