Is CBS p.Phe99Leu (c.297C>G) pathogenic?

CBS p.Phe99Leu (c.297C>G) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely pathogenic (0.7098); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Phe99Leu (c.297C>G)?

CBS p.Phe99Leu (c.297C>G) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (ClinVar).

How common is CBS p.Phe99Leu (c.297C>G) in the general population?

CBS p.Phe99Leu (c.297C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Phe99Leu (c.297C>G)?

AlphaMissense predicts likely pathogenic (score 0.7098) — an in-silico prediction, not a clinical call.

CBS p.Phe99Leu

c.297C>G · rs749697783 · VCV236937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7098 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.7098	likely pathogenic
REVEL	0.289	benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -2.8
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	0.163	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.Phe99Leu
Coding: c.297C>G
MANE Select: NM_000071
dbSNP: rs749697783
Type: single nucleotide variant
Location: chr21:43068528 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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.Phe99= Likely benign ★★ same residue
CBS p.Phe99Ser Uncertain significance ★ ⚠ same residue
CBS p.Phe99Tyr 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.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-phe99leu (accessed [today's date]).

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