Is ADA2 p.Ala427fs (c.1278dup) pathogenic?

ADA2 p.Ala427fs (c.1278dup) is classified Likely pathogenic in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Ala427fs (c.1278dup)?

ADA2 p.Ala427fs (c.1278dup) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How is Deficiency of adenosine deaminase 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ADA2 p.Ala427fs

c.1278dup · VCV3341408

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP 0.068, phastCons 0.96

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: ADA2
Protein: p.Ala427fs
Coding: c.1278dup
MANE Select: NM_001166105 · reported on NM_001282225
Type: Duplication
Location: chr22:17181983 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 427: the swirm domain; a DNA-binding region

Full ADA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

deficiency of adenosine deaminase 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Deficiency of adenosine deaminase 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ADA2 p.Arg49fs Pathogenic ★ same condition
ADA2 p.Gly25fs Likely pathogenic ★ same condition
ADA2 p.Met477fs Pathogenic ★ same condition
ADA2 p.Asn491fs Conflicting classifications of pathogenicity ★ same condition
ADA2 p.Thr380dup Conflicting classifications of pathogenicity ★ same condition
ADA2 c.973-20_973-16dup Likely benign ★ same condition
ADA2 c.754-2A>G Likely pathogenic ★★ same condition
ADA2 c.882-2A>G 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/ada2-p-ala427fs (accessed [today's date]).

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