Is BCAT1 p.Tyr227Cys (c.680A>G) pathogenic?

BCAT1 p.Tyr227Cys (c.680A>G) is classified Uncertain significance in BCAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.7625); Ultra-rare (popmax 0.049%, eas).

How common is BCAT1 p.Tyr227Cys (c.680A>G) in the general population?

BCAT1 p.Tyr227Cys (c.680A>G) is ultra-rare (popmax 0.049%, eas) (gnomAD).

What do computational predictors say about BCAT1 p.Tyr227Cys (c.680A>G)?

AlphaMissense predicts likely pathogenic (score 0.7625) — an in-silico prediction, not a clinical call.

BCAT1 p.Tyr227Cys

c.680A>G · rs556353032 · VCV3133344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7625 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7625	likely pathogenic
REVEL	0.708	pathogenic-leaning
SaProt	LLR -13.67	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 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 131 kb · p 0.77 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.049% East Asian · 22/44,882 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.00149% 24/1,613,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.049%	2,040
Admixed American	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: BCAT1
Protein: p.Tyr227Cys
Coding: c.680A>G
MANE Select: NM_005504
dbSNP: rs556353032
Type: single nucleotide variant
Location: chr12:24842219 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.05 · 17 PDB
Residue 227: a turn

Full BCAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAT1 p.Thr13= Benign ★★ same type
BCAT1 c.7-1070G>A Uncertain significance ★ same type
BCAT1 c.7-1075C>T Uncertain significance ★ same type
BCAT1 c.7-1078C>T Uncertain significance ★ same type
BCAT1 c.7-1082G>T Uncertain significance ★ same type
BCAT1 c.7-1091C>T Uncertain significance ★ same type
BCAT1 p.Ala27Thr Uncertain significance ★ ⚠ same type
BCAT1 p.Ala298Thr Uncertain significance ★ ⚠ 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/bcat1-p-tyr227cys (accessed [today's date]).

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