Is CBS p.Ser349Thr (c.1046G>C) pathogenic?

CBS p.Ser349Thr (c.1046G>C) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-24). AlphaMissense: ambiguous (0.3583); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Ser349Thr (c.1046G>C)?

CBS p.Ser349Thr (c.1046G>C) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (ClinVar).

How common is CBS p.Ser349Thr (c.1046G>C) in the general population?

CBS p.Ser349Thr (c.1046G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Ser349Thr (c.1046G>C)?

AlphaMissense predicts ambiguous (score 0.3583) — an in-silico prediction, not a clinical call.

CBS p.Ser349Thr

c.1046G>C · VCV3339154

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3583 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.3583	ambiguous
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -11.79	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 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	25.9	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.Ser349Thr
Coding: c.1046G>C
MANE Select: NM_000071
Type: single nucleotide variant
Location: chr21:43060540 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 349: an α-helix; a binding site; a UniProt-annotated variant site (in cbsd; severe form; exhibits an activity lower than 4% of the wild-type enzyme; absent 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

Similar variants

CBS p.Ser349Arg Likely pathogenic ★ same residue
CBS p.Ser349Gly Likely pathogenic ★ same residue
CBS p.Ser349Asn Likely pathogenic ★ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1552+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.451+1G>T Likely pathogenic ★★ same condition
CBS c.531+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-ser349thr (accessed [today's date]).

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