Is ABL1 p.Ala666Pro (c.1996G>C) pathogenic?

ABL1 p.Ala666Pro (c.1996G>C) is classified Uncertain significance in ABL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0918); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ABL1 p.Ala666Pro (c.1996G>C)?

ABL1 p.Ala666Pro (c.1996G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ABL1 p.Ala666Pro (c.1996G>C) in the general population?

ABL1 p.Ala666Pro (c.1996G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ABL1 p.Ala666Pro (c.1996G>C)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

ABL1 p.Ala666Pro

c.1996G>C · VCV4564728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.83	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 2.9	GERP -0.62, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,156 bp · p 0.054 · regional, not allelic
Overall
CADD	20.4	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 0.00017% European (non-Finnish) · 2/1,176,312 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,453,340 alleles · very rare

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.Ala666Pro
Coding: c.1996G>C
MANE Select: NM_005157
Type: single nucleotide variant
Location: chr9:130884286 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 85 PDB
Residue 666: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABL1 p.Ala767Val Uncertain significance ★★ ⚠ same condition
ABL1 p.Arg1016His Uncertain significance ★★ ⚠ same condition
ABL1 p.Arg771Gly Uncertain significance ★★ ⚠ same condition
ABL1 p.Asn1088His Uncertain significance ★★ ⚠ same condition
ABL1 p.Asn120Thr Uncertain significance ★★ ⚠ same condition
ABL1 p.Asn414Lys Uncertain significance ★★ ⚠ same condition
ABL1 p.Glu123Gln Uncertain significance ★★ ⚠ same condition
ABL1 p.Gly677Arg Uncertain significance ★★ ⚠ 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-ala666pro (accessed [today's date]).

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