Is ABL1 p.Val228Ala (c.683T>C) pathogenic?

ABL1 p.Val228Ala (c.683T>C) is classified Uncertain significance in ABL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely pathogenic (0.9341); Absent from gnomAD v4.1; Associated with congenital heart defects and skeletal malformations syndrome.

What condition is associated with ABL1 p.Val228Ala (c.683T>C)?

ABL1 p.Val228Ala (c.683T>C) is associated with congenital heart defects and skeletal malformations syndrome (ClinVar).

How common is ABL1 p.Val228Ala (c.683T>C) in the general population?

ABL1 p.Val228Ala (c.683T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABL1 p.Val228Ala (c.683T>C)?

AlphaMissense predicts likely pathogenic (score 0.9341) — an in-silico prediction, not a clinical call.

ABL1 p.Val228Ala

c.683T>C · rs2490695370 · VCV3068519

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9341 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital heart defects and skeletal malformations syndrome

Computational evidence

Protein change
AlphaMissense	0.9341	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -5.65	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	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.Val228Ala
Coding: c.683T>C
MANE Select: NM_005157
dbSNP: rs2490695370
Type: single nucleotide variant
Location: chr9:130862896 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 85 PDB
Residue 228: a β-strand

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

Disease context

congenital heart defects and skeletal malformations syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Marfanoid habitus-facial dysmorphism-skeletal abnormality-heart defect syndrome (Orphanet):

Onset: Neonatal

Similar variants

ABL1 p.Val228Gly Uncertain significance ★★ same residue
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

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-val228ala (accessed [today's date]).

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