Is ADA p.Asp19Glu (c.57C>A) pathogenic?

ADA p.Asp19Glu (c.57C>A) is classified Uncertain significance in ADA (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-31). AlphaMissense: likely pathogenic (0.9396); Very rare (popmax 6.21e-05%); 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.Asp19Glu (c.57C>A) in the general population?

ADA p.Asp19Glu (c.57C>A) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about ADA p.Asp19Glu (c.57C>A)?

AlphaMissense predicts likely pathogenic (score 0.9396) — an in-silico prediction, not a clinical call.

ADA p.Asp19Glu

Q: What condition is associated with ADA p.Asp19Glu (c.57C>A)?

ADA p.Asp19Glu (c.57C>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.57C>A · rs762695968 · VCV642970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

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	0.9396	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -8.78	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 2.5	GERP -1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	19.22	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 6.21e-05%

Overall 6.21e-05% 1/1,609,504 alleles · very rare exomes 1/1,457,196 · genomes 0/152,308 · 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.Asp19Glu
Coding: c.57C>A
MANE Select: NM_000022
dbSNP: rs762695968
Type: single nucleotide variant
Location: chr20:44636265 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 19: a binding site; 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.Asp19= Likely benign ★ same residue
ADA p.Asp19Val 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
ADA c.976-1G>C 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-asp19glu (accessed [today's date]).

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