Is ADA2 p.Arg312Ter (c.934C>T) pathogenic?

ADA2 p.Arg312Ter (c.934C>T) is classified Pathogenic in ADA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-13). Very rare (popmax 0.00801%, afr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Arg312Ter (c.934C>T)?

ADA2 p.Arg312Ter (c.934C>T) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome (ClinVar).

How common is ADA2 p.Arg312Ter (c.934C>T) in the general population?

ADA2 p.Arg312Ter (c.934C>T) is very rare (popmax 0.00801%, 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.Arg312Ter

c.934C>T · rs368615054 · VCV852411

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	Δ0.40	donor loss · deltas
Pangolin	Δ0.41	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.6	GERP 0.32, phastCons 0.19
Overall
CADD	36.0	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 0.00801% African / African-American · 6/74,906 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00167% 27/1,613,844 alleles · very rare exomes 19/1,461,694 · genomes 8/152,150 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,484
East Asian	0.00223%	44,886
European (non-Finnish)	0.0017%	58,995

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.Arg312Ter
Coding: c.934C>T
MANE Select: NM_001282225
dbSNP: rs368615054
Type: single nucleotide variant
Location: chr22:17189980 (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.Arg312Gln Uncertain significance ★★ ⚠ same residue
ADA2 p.Arg312Pro 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-arg312ter (accessed [today's date]).

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