Is ADA p.Pro126Gln (c.377C>A) pathogenic?

ADA p.Pro126Gln (c.377C>A) is classified Likely pathogenic in ADA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-26). AlphaMissense: likely pathogenic (0.6822); Very rare (popmax 0.000867%, nfe); 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.Pro126Gln (c.377C>A) in the general population?

ADA p.Pro126Gln (c.377C>A) is very rare (popmax 0.000867%, nfe) (gnomAD).

What do computational predictors say about ADA p.Pro126Gln (c.377C>A)?

AlphaMissense predicts likely pathogenic (score 0.6822) — an in-silico prediction, not a clinical call.

ADA p.Pro126Gln

Q: What condition is associated with ADA p.Pro126Gln (c.377C>A)?

ADA p.Pro126Gln (c.377C>A) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, severe combined immunodeficiency (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.377C>A · rs1233957241 · VCV842419

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000867%, nfe)

Missense predictors

3/3 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	0.6822	likely pathogenic ✓ concordant with ClinVar
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	29.6	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 0.000867% European (non-Finnish) · 10/1,153,442 alleles

Filtering AF 0.000438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00032%

Overall 0.000639% 10/1,563,916 alleles · very rare exomes 9/1,411,710 · genomes 1/152,206 · 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.Pro126Gln
Coding: c.377C>A
MANE Select: NM_000022
dbSNP: rs1233957241
Type: single nucleotide variant
Location: chr20:44625670 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 126: the 'required for binding to ddp4' region; 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

Also linked: severe combined immunodeficiency

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 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
ADA p.Arg149Trp Likely 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-pro126gln (accessed [today's date]).

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