Is ADA p.Trp117Arg (c.349T>C) pathogenic?

ADA p.Trp117Arg (c.349T>C) is classified Uncertain significance in ADA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-11-02). AlphaMissense: likely pathogenic (0.8762); Ultra-rare (popmax 0.0217%, amr); 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.Trp117Arg (c.349T>C) in the general population?

ADA p.Trp117Arg (c.349T>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ADA p.Trp117Arg (c.349T>C)?

AlphaMissense predicts likely pathogenic (score 0.8762) — an in-silico prediction, not a clinical call.

ADA p.Trp117Arg

Q: What condition is associated with ADA p.Trp117Arg (c.349T>C)?

ADA p.Trp117Arg (c.349T>C) 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.349T>C · rs771162170 · VCV1046026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

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	0.8762	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -1.65	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	29.4	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 0.0217% Admixed American · 13/59,998 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000806% 13/1,613,840 alleles · ultra-rare exomes 11/1,461,668 · genomes 2/152,172 · joint denominator

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.Trp117Arg
Coding: c.349T>C
MANE Select: NM_000022
dbSNP: rs771162170
Type: single nucleotide variant
Location: chr20:44626469 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 117: 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.Trp117Ter 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
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-trp117arg (accessed [today's date]).

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