Is ABL1 p.Asn331Ser (c.992A>G) pathogenic?

ABL1 p.Asn331Ser (c.992A>G) is classified Conflicting classifications of pathogenicity in ABL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-13). AlphaMissense: likely benign (0.0655); Ultra-rare (popmax 0.0467%, afr); Associated with congenital heart defects and skeletal malformations syndrome.

What condition is associated with ABL1 p.Asn331Ser (c.992A>G)?

ABL1 p.Asn331Ser (c.992A>G) is associated with congenital heart defects and skeletal malformations syndrome (ClinVar).

How common is ABL1 p.Asn331Ser (c.992A>G) in the general population?

ABL1 p.Asn331Ser (c.992A>G) is ultra-rare (popmax 0.0467%, afr) (gnomAD).

What do computational predictors say about ABL1 p.Asn331Ser (c.992A>G)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

ABL1 p.Asn331Ser

c.992A>G · rs144448357 · VCV2187293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital heart defects and skeletal malformations syndrome

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 10 kb · p 1.5e-16 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.0467% African / African-American · 35/75,012 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00396% 64/1,614,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0467%	2,143
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asian	0.00446%	22,444
South Asian	0.00439%	22,770
Finnishnot grpmax-eligible	0.00156%	64,040
European (non-Finnish)	0.00153%	65,557

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.Asn331Ser
Coding: c.992A>G
MANE Select: NM_005157
dbSNP: rs144448357
Type: single nucleotide variant
Location: chr9:130872944 (GRCh38)
Gene constraint: LOEUF 0.19 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 85 PDB
Residue 331: the protein kinase domain

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.Asn331Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
ABL1 p.Asn331Ile Uncertain significance ★ ⚠ same residue
ABL1 p.Asn331Thr Likely benign ★ ⚠ 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-asn331ser (accessed [today's date]).

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