Is CBS p.Thr191Lys (c.572C>A) pathogenic?

CBS p.Thr191Lys (c.572C>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-07). AlphaMissense: likely pathogenic (0.9673); Absent from gnomAD v4.1.

How common is CBS p.Thr191Lys (c.572C>A) in the general population?

CBS p.Thr191Lys (c.572C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Thr191Lys (c.572C>A)?

AlphaMissense predicts likely pathogenic (score 0.9673) — an in-silico prediction, not a clinical call.

CBS p.Thr191Lys

c.572C>A · rs121964973 · VCV431934

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9673 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9673	likely pathogenic · top 7% in CBS
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	27.9	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.Thr191Lys
Coding: c.572C>A
MANE Select: NM_000071
dbSNP: rs121964973
Type: single nucleotide variant
Location: chr21:43065481 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 191: a β-strand; a UniProt-annotated variant site (in cbsd; moderate and severe forms; loss of cystathionine beta-synthase activity; absent capacity to form multimeric quaternary structure)

Full CBS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBS p.Thr191Met Pathogenic ★★ same residue
CBS p.Thr191= Benign/Likely benign ★★ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same type
CBS c.1223+1G>T Pathogenic ★★ same type
CBS c.1224-2A>C Pathogenic ★★ same type
CBS c.1358+1G>A Pathogenic ★★ same type
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same type
CBS c.1468-1G>A Likely pathogenic ★★ same type

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-thr191lys (accessed [today's date]).

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