Is ADA p.Ala329Val (c.986C>T) pathogenic?

ADA p.Ala329Val (c.986C>T) is classified Pathogenic in ADA (ClinVar, Expert panel, 17 submitters; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.8763); Ultra-rare (popmax 0.0494%, afr); 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.Ala329Val (c.986C>T) in the general population?

ADA p.Ala329Val (c.986C>T) is ultra-rare (popmax 0.0494%, afr) (gnomAD).

What do computational predictors say about ADA p.Ala329Val (c.986C>T)?

AlphaMissense predicts likely pathogenic (score 0.8763) — an in-silico prediction, not a clinical call.

ADA p.Ala329Val

Q: What condition is associated with ADA p.Ala329Val (c.986C>T)?

ADA p.Ala329Val (c.986C>T) 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, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (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.986C>T · rs121908715 · VCV1959

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.8763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, afr)

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):

PM6_Moderate PP4_Moderate PM2_Supporting PS3_Moderate PM3_Strong

Curation rationale (ClinGen, verbatim)

The c.986C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 329 (p.Ala329Val). The filtering allele frequency (the upper threshold of the 95% CI of 37/74910) of the c.986C>T variant in ADA is 0.0003683 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore do not meet this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. In vitro experiments of ADA activity in E. coli demonstrated a percentage of wild-type (wt) activity ranging from 0.1% to 5.1%, with an average ± standard deviation of 1.2% ± 1.4%. This finding classifies the variant into Group I, suggesting a significant impact on protein function. (PS3_Moderate; PMID 9758612). This variant has been detected in many individuals in the literature. Evaluated here four patients with ADA-SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant: * PMID 8614422, compound heterozygous with p.Gly74Val (at least likely pathogenic according to SCID VCEP specifications, Phase is not confirmed = 0.25pt; * PMID 32307643, compound heterozygous with p.Ser291Leu (at least likely pathogenic according to SCID VCEP specifications. Phase is not confirmed = 0.25pt; * PMID: 8401541, Proband 1 is comp. het. A329V and Q254X (at least likely pathogenic according to SCID VCEP specifications - PM2_Supporting and PVS1) - phase (in trans) confirmed = 1pt; Additionally, 01 individual was homozygous for the variant = 0.5 pts (PMID: 1346349). The total is 2 points, PM3_Strong. Patient from PMID 8614422 presented: * ADA activity in patient RBCs was undetectable (1pt), * Concentration of total deoxyadenosine nucleotides was elevated (2pt). * ADA-SCID phenotypes of the patient were corrected by PEG-ADA supplement (1pt). Total = 4 points, PP4_Moderate. PMID: 8614422. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 01 individual with ADA-SCID, with phenotype highly specific for the gene (PM6_Moderate, PMID: 1346349). In summary, this variant is classified as Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PS3_Moderate, PM3_Strong, PP4_Moderate, and PM6_Moderate.

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

Computational evidence

Protein change
AlphaMissense	0.8763	likely pathogenic ✓ concordant with ClinVar
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -13.98	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 0.49, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	29.2	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 0.0494% African / African-American · 37/74,910 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.00366% 59/1,613,978 alleles · ultra-rare exomes 31/1,461,794 · genomes 28/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0494%	2,025
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,888
European (non-Finnish)	0.00136%	73,748
South Asian	0.0011%	91,096

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.Ala329Val
Coding: c.986C>T
MANE Select: NM_000022
dbSNP: rs121908715
Type: single nucleotide variant
Location: chr20:44620391 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 329: an α-helix; a UniProt-annotated variant site (in adascid)

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, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

For Severe combined immunodeficiency due to adenosine deaminase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

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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-ala329val (accessed [today's date]).

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