Is ADA2 p.Phe355Leu (c.1065C>A) pathogenic?

ADA2 p.Phe355Leu (c.1065C>A) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.6625); Rare (popmax 0.397%, eas); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Phe355Leu (c.1065C>A)?

ADA2 p.Phe355Leu (c.1065C>A) is associated with autoinflammatory syndrome, Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Phe355Leu (c.1065C>A) in the general population?

ADA2 p.Phe355Leu (c.1065C>A) is rare (popmax 0.397%, eas) (gnomAD).

What do computational predictors say about ADA2 p.Phe355Leu (c.1065C>A)?

AlphaMissense predicts likely pathogenic (score 0.6625) — an in-silico prediction, not a clinical call.

ADA2 p.Phe355Leu

c.1065C>A · rs116020027 · VCV859452

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6625 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.397%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.6625	likely pathogenic
REVEL	0.502	indeterminate
SaProt	LLR -10.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.39, phastCons 1
Overall
CADD	17.34	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 0.397% East Asian · 178/44,868 alleles

Filtering AF 0.349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.331%

Overall 0.0132% 213/1,613,756 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.397%	252
Remaining individualsnot grpmax-eligible	0.0272%	3,676
South Asian	0.0176%	5,692
Admixed American	0.00333%	30,015

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.Phe355Leu
Coding: c.1065C>A
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs116020027
Type: single nucleotide variant
Location: chr22:17188355 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 355: the 'disordered' region

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

TADA2A p.Ser355Leu Uncertain significance ★ ⚠ same residue
ADA2 c.754-2A>G Likely pathogenic ★★ same condition
ADA2 c.882-2A>G Pathogenic ★★ same condition
ADA2 c.973-2A>G Pathogenic ★★ same condition
ADA2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Arg169Trp Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Arg306Ter Likely pathogenic ★★ same condition
ADA2 p.Arg312Ter 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-phe355leu (accessed [today's date]).

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