Is ADA2 p.Leu475= (c.1423C>T) pathogenic?

ADA2 p.Leu475= (c.1423C>T) is classified Likely benign in ADA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-15). Rare (popmax 0.103%, afr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Leu475= (c.1423C>T)?

ADA2 p.Leu475= (c.1423C>T) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome (ClinVar).

How common is ADA2 p.Leu475= (c.1423C>T) in the general population?

ADA2 p.Leu475= (c.1423C>T) is rare (popmax 0.103%, afr) (gnomAD).

How is Deficiency of adenosine deaminase 2 inherited?

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

ADA2 p.Leu475=

c.1423C>T · rs138076444 · VCV786263

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.103%, afr)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.92, phastCons 0.99
Overall
CADD	5.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% African / African-American · 77/74,932 alleles

Filtering AF 0.0842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0774%

Overall 0.0057% 92/1,613,460 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.103%	973
South Asian	0.0121%	8,279
Remaining individualsnot grpmax-eligible	0.00641%	15,609

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.Leu475=
Coding: c.1423C>T
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs138076444
Type: single nucleotide variant
Location: chr22:17181839 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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

Also linked: Sneddon syndrome

For Deficiency of adenosine deaminase 2 (Orphanet):

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

Similar variants

ADA2 p.Leu475Met 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-leu475 (accessed [today's date]).

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