Is ADA2 p.Arg306Ter (c.916C>T) pathogenic?

ADA2 p.Arg306Ter (c.916C>T) is classified Likely pathogenic in ADA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-16). Ultra-rare (popmax 0.0164%, mid); Associated with ADA2 & CECR1-related disorders.

What condition is associated with ADA2 p.Arg306Ter (c.916C>T)?

ADA2 p.Arg306Ter (c.916C>T) is associated with ADA2 & CECR1-related disorders, Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Arg306Ter (c.916C>T) in the general population?

ADA2 p.Arg306Ter (c.916C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

ADA2 p.Arg306Ter

c.916C>T · rs774963498 · VCV636596

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

ADA2 & CECR1-related disorders

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	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.43	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.41	GERP 0.28, phastCons 0.012
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000991% 16/1,613,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,991
European (non-Finnish)	0.00102%	98,322

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.Arg306Ter
Coding: c.916C>T
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs774963498
Type: single nucleotide variant
Location: chr22:17189998 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

Full ADA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ADA2 & CECR1-related disorders

Also linked: Sneddon syndrome deficiency of adenosine deaminase 2

Similar variants

ADA2 p.Arg306Gln Uncertain significance ★★ ⚠ same residue
ADA2 p.Arg306Gly 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.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-arg306ter (accessed [today's date]).

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