Is ABL1 p.Pro784Arg (c.2351C>G) pathogenic?

ABL1 p.Pro784Arg (c.2351C>G) is classified Uncertain significance in ABL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.32); Very rare (popmax 0.00446%, eas); Associated with congenital heart defects and skeletal malformations syndrome.

What condition is associated with ABL1 p.Pro784Arg (c.2351C>G)?

ABL1 p.Pro784Arg (c.2351C>G) is associated with congenital heart defects and skeletal malformations syndrome (ClinVar).

How common is ABL1 p.Pro784Arg (c.2351C>G) in the general population?

ABL1 p.Pro784Arg (c.2351C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ABL1 p.Pro784Arg (c.2351C>G)?

AlphaMissense predicts likely benign (score 0.32) — an in-silico prediction, not a clinical call.

ABL1 p.Pro784Arg

c.2351C>G · rs1355021408 · VCV1333299

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.32 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital heart defects and skeletal malformations syndrome

Computational evidence

Protein change
AlphaMissense	0.32	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.94, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,156 bp · p 0.054 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00124% 20/1,613,138 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
Admixed American	0.00333%	30,000
South Asian	0.00329%	30,363
African / African-American	0.00133%	74,918
European (non-Finnish)	0.00102%	98,333

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: ABL1
Protein: p.Pro784Arg
Coding: c.2351C>G
MANE Select: NM_005157
dbSNP: rs1355021408
Type: single nucleotide variant
Location: chr9:130884641 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 85 PDB
Residue 784: the 'disordered' region

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.Pro784Leu Likely pathogenic ★ ⚠ same residue
ABL1 p.Pro784= Benign ★★ same residue
ABL1 p.Pro784Ala Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro784arg (accessed [today's date]).

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