Is ABL1 p.Tyr226Cys (c.677A>G) pathogenic?

ABL1 p.Tyr226Cys (c.677A>G) is classified Pathogenic/Likely pathogenic in ABL1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-25). AlphaMissense: likely pathogenic (0.666); Absent from gnomAD v4.1; Associated with congenital heart disease.

What condition is associated with ABL1 p.Tyr226Cys (c.677A>G)?

ABL1 p.Tyr226Cys (c.677A>G) is associated with congenital heart disease, congenital heart defects and skeletal malformations syndrome (ClinVar).

How common is ABL1 p.Tyr226Cys (c.677A>G) in the general population?

ABL1 p.Tyr226Cys (c.677A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABL1 p.Tyr226Cys (c.677A>G)?

AlphaMissense predicts likely pathogenic (score 0.666) — an in-silico prediction, not a clinical call.

ABL1 p.Tyr226Cys

c.677A>G · rs1060499547 · VCV374795

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.666 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital heart disease

Computational evidence

Protein change
AlphaMissense	0.666	likely pathogenic ✓ concordant with ClinVar
REVEL	0.674	pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 10 kb · p 1.5e-16 · regional, not allelic
Overall
CADD	28.9	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: ABL1
Protein: p.Tyr226Cys
Coding: c.677A>G
MANE Select: NM_005157
dbSNP: rs1060499547
Type: single nucleotide variant
Location: chr9:130862890 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 85 PDB
Residue 226: a β-strand; a modified residue (phosphotyrosine; by autocatalysis); a UniProt-annotated variant site (in chdskm; increases kinase activity; no effect on protein levels)

Full ABL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital heart disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital heart defects and skeletal malformations syndrome

Similar variants

ABL1 p.Ala337Thr Pathogenic ★★ ⚠ same condition
ABL1 p.Ala433Thr Likely pathogenic ★★ same condition
ABL1 p.Asp504Gly Likely pathogenic ★★ ⚠ same condition
ABL1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same condition
ABL1 p.Gly254Arg Pathogenic/Likely pathogenic ★★ same condition
ABL1 p.Pro230Leu Likely pathogenic ★★ same condition
ABL1 p.Trp99Arg Likely pathogenic ★★ same condition
ABL1 p.Val506Ala Pathogenic/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/abl1-p-tyr226cys (accessed [today's date]).

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