Is ADA2 p.Lys466fs (c.1397_1403del) pathogenic?

ADA2 p.Lys466fs (c.13971403del) is classified Pathogenic/Likely pathogenic in ADA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-31). Ultra-rare (popmax 0.0167%, mid); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Lys466fs (c.1397_1403del)?

ADA2 p.Lys466fs (c.1397_1403del) is associated with autoinflammatory syndrome, Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Lys466fs (c.1397_1403del) in the general population?

ADA2 p.Lys466fs (c.1397_1403del) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

ADA2 p.Lys466fs

c.1397_1403del · rs754904956 · VCV860051

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

autoinflammatory syndrome

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 0.75	GERP 0.13, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,986 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,613,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,986
Admixed American	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)	0.000339%	295,003

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: ADA2
Protein: p.Lys466fs
Coding: c.1397_1403del
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs754904956
Type: Deletion
Location: chr22:17181859 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Sneddon syndrome deficiency of adenosine deaminase 2

Similar variants

ADA2 p.Ala221fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Asn53fs Pathogenic ★★ same condition
ADA2 p.His434_Pro435insTer Pathogenic ★★ same condition
ADA2 p.Lys314fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Tyr353fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 c.754-12del Likely benign ★★ same condition
ADA2 c.882-11del Benign/Likely benign ★★ same condition
ADA2 c.972+7del Likely benign ★★ 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-lys466fs (accessed [today's date]).

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