Is ADA2 p.Lys314fs (c.940_941del) pathogenic?

ADA2 p.Lys314fs (c.940941del) is classified Pathogenic/Likely pathogenic in ADA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00667%, amr); Associated with Sneddon syndrome.

What condition is associated with ADA2 p.Lys314fs (c.940_941del)?

ADA2 p.Lys314fs (c.940_941del) is associated with Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Lys314fs (c.940_941del) in the general population?

ADA2 p.Lys314fs (c.940_941del) is very rare (popmax 0.00667%, amr) (gnomAD).

How is Sneddon syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ADA2 p.Lys314fs

c.940_941del · rs768987774 · VCV1411116

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Sneddon 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 0.036	GERP -2.4, phastCons 0.005
Overall
CADD	16.1	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 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,928 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,000
European (non-Finnish)	8.48e-05%	1,179,906

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.Lys314fs
Coding: c.940_941del
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs768987774
Type: Deletion
Location: chr22:17189973 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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

Disease context

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

Also linked: deficiency of adenosine deaminase 2

For Sneddon syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

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.Lys466fs 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-lys314fs (accessed [today's date]).

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