Is ADA2 p.Leu183Pro (c.548T>C) pathogenic?

ADA2 p.Leu183Pro (c.548T>C) is classified Likely pathogenic in ADA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.667); Very rare (popmax 6.2e-05%); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Leu183Pro (c.548T>C)?

ADA2 p.Leu183Pro (c.548T>C) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome (ClinVar).

How common is ADA2 p.Leu183Pro (c.548T>C) in the general population?

ADA2 p.Leu183Pro (c.548T>C) is very rare (popmax 6.2e-05%) (gnomAD).

How is Deficiency of adenosine deaminase 2 inherited?

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

What do computational predictors say about ADA2 p.Leu183Pro (c.548T>C)?

AlphaMissense predicts likely pathogenic (score 0.667) — an in-silico prediction, not a clinical call.

ADA2 p.Leu183Pro

c.548T>C · rs2517346966 · VCV1691821

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.667	likely pathogenic ✓ concordant with ClinVar
REVEL	0.517	indeterminate
SaProt	LLR -11.02	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 3.6	GERP -2.1, phastCons 0.97
Overall
CADD	21.8	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 6.2e-05%

Overall 6.2e-05% 1/1,612,924 alleles · very rare exomes 1/1,460,572 · genomes 0/152,352 · joint denominator

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.Leu183Pro
Coding: c.548T>C
MANE Select: NM_001282225
dbSNP: rs2517346966
Type: single nucleotide variant
Location: chr22:17203768 (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.Leu183= Likely benign ★ same residue
TADA2A p.Ala183Val 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

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-leu183pro (accessed [today's date]).

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