Is ADA p.Arg76Trp (c.226C>T) pathogenic?

ADA p.Arg76Trp (c.226C>T) is classified Conflicting classifications of pathogenicity in ADA (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.2815); Rare (popmax 0.295%, 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.Arg76Trp (c.226C>T) in the general population?

ADA p.Arg76Trp (c.226C>T) is rare (popmax 0.295%, afr) (gnomAD).

What do computational predictors say about ADA p.Arg76Trp (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2815) — an in-silico prediction, not a clinical call.

ADA p.Arg76Trp

Q: What condition is associated with ADA p.Arg76Trp (c.226C>T)?

ADA p.Arg76Trp (c.226C>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.226C>T · rs121908736 · VCV1962

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.2815 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.295%, 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

Computational evidence

Protein change
AlphaMissense	0.2815	likely benign
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -12.29	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 5.7	GERP 0.34, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	29.5	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 0.295% African / African-American · 221/75,012 alleles

Filtering AF 0.263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.25%

Overall 0.0188% 304/1,613,988 alleles · rare exomes 186/1,461,790 · genomes 118/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.295%	339
Remaining individualsnot grpmax-eligible	0.04%	2,500
Middle Eastern	0.0332%	3,011
Admixed American	0.025%	4,001
South Asian	0.0154%	6,505
East Asian	0.00223%	44,864
European (non-Finnish)	0.0022%	45,384

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.Arg76Trp
Coding: c.226C>T
MANE Select: NM_000022
dbSNP: rs121908736
Type: single nucleotide variant
Location: chr20:44626592 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 76: a UniProt-annotated variant site (in adascid); an α-helix

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.Arg76Gln 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
ADA c.976-1G>C Pathogenic ★★★ same condition
ADA p.Ala329Val 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-arg76trp (accessed [today's date]).

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