Is ADA p.Arg149Gln (c.446G>A) pathogenic?

ADA p.Arg149Gln (c.446G>A) is classified Uncertain significance in ADA (ClinVar, Expert panel, 7 submitters; last evaluated 2023-11-14). AlphaMissense: likely benign (0.2146); Ultra-rare (popmax 0.0121%, afr); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

How common is ADA p.Arg149Gln (c.446G>A) in the general population?

ADA p.Arg149Gln (c.446G>A) is ultra-rare (popmax 0.0121%, afr) (gnomAD).

What do computational predictors say about ADA p.Arg149Gln (c.446G>A)?

AlphaMissense predicts likely benign (score 0.2146) — an in-silico prediction, not a clinical call.

ADA p.Arg149Gln

Q: What condition is associated with ADA p.Arg149Gln (c.446G>A)?

ADA p.Arg149Gln (c.446G>A) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (ClinVar).

Q: How is Severe combined immunodeficiency due to adenosine deaminase deficiency inherited?

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

c.446G>A · rs121908737 · VCV1963

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Uncertain Significance for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):

PM5_Supporting BS3_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000022.4(ADA):c.446G>A (p.Arg149Gln) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 149 (p.Arg149Gln). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/107374 observed alleles) is 0.000003610 on gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742). However, we can not use this evidence because it has a filter warning (RF). Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612, BS3_moderate). At least one additional missense variant was observed as LP according to SCID VCEP specifications version (PM5_supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS3_Supporting, and PM5_Suppoting. (VCEP specifications version 1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2146	likely benign
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -14.47	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.25, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	29.9	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 0.0121% African / African-American · 9/74,646 alleles

Filtering AF 0.00626% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.00214% 34/1,588,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0121%	8,294
Remaining individualsnot grpmax-eligible	0.00488%	20,490
European (non-Finnish)	0.00188%	53,077

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: ADA
Protein: p.Arg149Gln
Coding: c.446G>A
MANE Select: NM_000022
dbSNP: rs121908737
Type: single nucleotide variant
Location: chr20:44625601 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 149: a UniProt-annotated variant site (in adascid; uncertain significance); a UniProt-annotated variant site (in adascid); a β-strand

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

Disease context

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to adenosine deaminase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ADA p.Arg149Trp Likely pathogenic ★★★ same residue
ADA p.Arg149= Conflicting classifications of pathogenicity ★ same residue
ADA p.Arg149Leu Uncertain significance ★ ⚠ same residue
ADA c.1078+2T>A Likely pathogenic ★★★ same condition
ADA c.219-2A>G Likely pathogenic ★★★ same condition
ADA c.363-2A>G Likely pathogenic ★★★ same condition
ADA c.606+1G>T Likely pathogenic ★★★ same condition
ADA c.975+1G>A 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/ada-p-arg149gln (accessed [today's date]).

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