Is CBS p.Ile95Thr (c.284T>C) pathogenic?

CBS p.Ile95Thr (c.284T>C) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-21). AlphaMissense: likely benign (0.1934); Very rare (popmax 0.00359%, amr); Associated with classic homocystinuria.

What condition is associated with CBS p.Ile95Thr (c.284T>C)?

CBS p.Ile95Thr (c.284T>C) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Ile95Thr (c.284T>C) in the general population?

CBS p.Ile95Thr (c.284T>C) is very rare (popmax 0.00359%, amr) (gnomAD).

What do computational predictors say about CBS p.Ile95Thr (c.284T>C)?

AlphaMissense predicts likely benign (score 0.1934) — an in-silico prediction, not a clinical call.

CBS p.Ile95Thr

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.284T>C · rs1347662650 · VCV471361

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00359%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.1934	likely benign
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -9.03	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.00359% Admixed American · 1/27,834 alleles

Filtering AF 0.000155% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.8e-05%

Overall 0.00112% 4/355,624 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00359%	27,834
East Asian	0.00343%	29,118
European (non-Finnish)	0.000933%	107,126

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.Ile95Thr
Coding: c.284T>C
MANE Select: NM_000071
dbSNP: rs1347662650
Type: single nucleotide variant
Location: chr21:43068541 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 95: an α-helix

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.Ile95Asn Likely pathogenic ★ same residue
CBS p.Ile95= 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-ile95thr (accessed [today's date]).

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