Is CBS p.Phe99Ser (c.296T>C) pathogenic?

CBS p.Phe99Ser (c.296T>C) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-24). AlphaMissense: likely benign (0.1513); Very rare (popmax 0.00583%, afr); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Phe99Ser (c.296T>C)?

CBS p.Phe99Ser (c.296T>C) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (ClinVar).

How common is CBS p.Phe99Ser (c.296T>C) in the general population?

CBS p.Phe99Ser (c.296T>C) is very rare (popmax 0.00583%, afr) (gnomAD).

What do computational predictors say about CBS p.Phe99Ser (c.296T>C)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

CBS p.Phe99Ser

c.296T>C · rs112029370 · VCV1516009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00583%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.8, phastCons 0.66
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	20.5	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

Grpmax group 0.00583% African / African-American · 1/17,138 alleles

Filtering AF 0.000162% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.1e-05%

Overall 0.000789% 3/380,042 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00583%	17,138
European (non-Finnish)	0.000975%	102,530

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CBS
Protein: p.Phe99Ser
Coding: c.296T>C
MANE Select: NM_000071
dbSNP: rs112029370
Type: single nucleotide variant
Location: chr21:43068529 (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.Phe99Leu 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-phe99ser (accessed [today's date]).

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