Is ADA p.Val129Met (c.385G>A) pathogenic?

ADA p.Val129Met (c.385G>A) is classified Pathogenic/Likely pathogenic in ADA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.822); Very rare (popmax 0.000519%, 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.Val129Met (c.385G>A) in the general population?

ADA p.Val129Met (c.385G>A) is very rare (popmax 0.000519%, nfe) (gnomAD).

What do computational predictors say about ADA p.Val129Met (c.385G>A)?

AlphaMissense predicts likely pathogenic (score 0.822) — an in-silico prediction, not a clinical call.

ADA p.Val129Met

Q: What condition is associated with ADA p.Val129Met (c.385G>A)?

ADA p.Val129Met (c.385G>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.385G>A · rs121908731 · VCV68260

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000519%, 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

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Pathogenic for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):

PP4_Moderate PM2_Supporting PM3_VeryStrong PS3_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000022.4(ADA):c.385G>A (p.Val129Met) variant in exon 5 of ADA is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 129 (p.Val129Met). The Grpmax filtering allele frequency of this variant in gnomAD v4.1.0 is 0.00000187, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed in gnomAD v4.1.0. (PM2_Supporting). Internal communication with Dr. Michael Hershfield indicated there are records of 2 homozygous patients with a delayed-onset CID phenotype-one cared for in Ottawa Canada and the other in Boston. Both patients are ADA- deficient and have elevated levels of red cell dAXP. One of these cases may correspond to the patient described in PMID: 32888943, given that the authors are also from Boston (1 point). This variant was also found in the homozygous state in three additional unrelated ADA-deficient probands (3 points; PMID: 31858364, 26255240). In addition, this variant was identified in compound heterozygous state in five unrelated ADA-deficient probands. The accompanying missense ADA variants were Gly140Arg (c.418G>A), Ser291Leu (c.872C>T), His15Asp (c.43C>G) and two variants not specified. The ADA variant Ser291Leu has been classified as likely pathogenic by the SCID expert panel, while the other two are VUS (1.5 points; PMID: 39052144, 32307643, 26376800 ). In total, the evidence sums to 5.5 points, therefore, PM3_very strong is met. 2 patients with delayed onset SCID were reported in PMID: 10200056. Patient "AR' (homozygous) was tested by sequencing of cDNA, amplified genomic DNA, SSCP of amplified genomic DNA. Increased dAdo nucleotides (dATP or dAXP) was observed in pretreatment erythrocytes (5 pt). Therefore, PP4_Moderate is met The residual enzyme activity for this variant was measured as 0.11+/-0.4% of wild-type. The strength of evidence from cellular models/in vitro studies is dependent upon the level of expressed ADA enzyme activity based on levels defined by Arredondo-Vega et al., 1998 (PMID: 9758612) and meets PS3_Supporting criteria. In summary, this variant meets the criteria to be classified as pathogenic for severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP4_Moderate, PM3_Very Strong, PM2_Supporting, and PS3_Supporting (VCEP specifications version 2.1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.822	likely pathogenic ✓ concordant with ClinVar
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -11.46	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	27.7	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 0.000519% European (non-Finnish) · 6/1,155,430 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000424% 6/1,415,356 alleles · very rare

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.Val129Met
Coding: c.385G>A
MANE Select: NM_000022
dbSNP: rs121908731
Type: single nucleotide variant
Location: chr20:44625662 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 129: the 'required for binding to ddp4' region; a UniProt-annotated variant site (in adascid; delayed-onset); 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.Val129Leu Likely pathogenic ★ same residue
ADA p.Val129= Likely benign ★ 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-val129met (accessed [today's date]).

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