Is ADA2 p.Asn127His (c.379A>C) pathogenic?

ADA2 p.Asn127His (c.379A>C) is classified Uncertain significance in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely benign (0.2105); Very rare (popmax 0.00446%, eas); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Asn127His (c.379A>C)?

ADA2 p.Asn127His (c.379A>C) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome (ClinVar).

How common is ADA2 p.Asn127His (c.379A>C) in the general population?

ADA2 p.Asn127His (c.379A>C) is very rare (popmax 0.00446%, eas) (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.Asn127His (c.379A>C)?

AlphaMissense predicts likely benign (score 0.2105) — an in-silico prediction, not a clinical call.

ADA2 p.Asn127His

c.379A>C · VCV3587773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.2105	likely benign
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -11.64	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Overall
CADD	23.9	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,480 alleles · very rare

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.Asn127His
Coding: c.379A>C
MANE Select: NM_001166105 · reported on NM_001282225
Type: single nucleotide variant
Location: chr22:17207234 (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.Asn127Ser 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-asn127his (accessed [today's date]).

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