Is ADA p.Arg253Trp (c.757C>T) pathogenic?

ADA p.Arg253Trp (c.757C>T) is classified Uncertain significance in ADA (ClinVar, Expert panel, 8 submitters; last evaluated 2024-01-10). AlphaMissense: likely benign (0.1797); Ultra-rare (popmax 0.0156%, eas); 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.Arg253Trp (c.757C>T) in the general population?

ADA p.Arg253Trp (c.757C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ADA p.Arg253Trp (c.757C>T)?

AlphaMissense predicts likely benign (score 0.1797) — an in-silico prediction, not a clinical call.

ADA p.Arg253Trp

Q: What condition is associated with ADA p.Arg253Trp (c.757C>T)?

ADA p.Arg253Trp (c.757C>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.757C>T · rs201944717 · VCV618516

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

ClinGen expert panel

Uncertain Significance — Severe Combined Immunodeficiency Disease VCEP (adenosine deaminase deficiency).

Computational evidence

Protein change
AlphaMissense	0.1797	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -11.35	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP -0.8, phastCons 0.87
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	21.8	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 0.0156% East Asian · 7/44,882 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00768% 124/1,614,188 alleles · ultra-rare exomes 115/1,461,892 · genomes 9/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
European (non-Finnish)	0.00856%	11,683
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.00549%	18,217
African / African-American	0.004%	25,018

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.Arg253Trp
Coding: c.757C>T
MANE Select: NM_000022
dbSNP: rs201944717
Type: single nucleotide variant
Location: chr20:44622852 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 253: 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.Arg253Gln Uncertain significance ★★ ⚠ same residue
ADA p.Arg253= Likely benign ★ same residue
ADA p.Arg253fs Likely pathogenic ★ 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-arg253trp (accessed [today's date]).

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