Is ADA p.Arg149Trp (c.445C>T) pathogenic?

ADA p.Arg149Trp (c.445C>T) is classified Likely pathogenic in ADA (ClinVar, Expert panel, 5 submitters; last evaluated 2023-10-10). AlphaMissense: ambiguous (0.4478); Very rare (popmax 0.00402%, 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.Arg149Trp (c.445C>T) in the general population?

ADA p.Arg149Trp (c.445C>T) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about ADA p.Arg149Trp (c.445C>T)?

AlphaMissense predicts ambiguous (score 0.4478) — an in-silico prediction, not a clinical call.

ADA p.Arg149Trp

Q: What condition is associated with ADA p.Arg149Trp (c.445C>T)?

ADA p.Arg149Trp (c.445C>T) 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.445C>T · rs121908733 · VCV68264

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

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

Likely Pathogenic for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):

PM2_Supporting PP4_Moderate PS3_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000022.4:c.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID: 10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0).

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

Computational evidence

Protein change
AlphaMissense	0.4478	ambiguous
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -17.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.32, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	28.0	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 0.00402% African / African-American · 3/74,552 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000656%

Overall 0.00126% 20/1,588,920 alleles · very rare exomes 18/1,436,750 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,851
Finnishnot grpmax-eligible	0.00161%	61,980
European (non-Finnish)	0.00137%	72,995

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: ADA
Protein: p.Arg149Trp
Coding: c.445C>T
MANE Select: NM_000022
dbSNP: rs121908733
Type: single nucleotide variant
Location: chr20:44625602 (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.Arg149Gln Uncertain significance ★★★ ⚠ 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-arg149trp (accessed [today's date]).

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