Is ADA p.Val96Ala (c.287T>C) pathogenic?

ADA p.Val96Ala (c.287T>C) is classified Uncertain significance in ADA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely benign (0.1987); Very rare (popmax 0.00134%, 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.Val96Ala (c.287T>C) in the general population?

ADA p.Val96Ala (c.287T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ADA p.Val96Ala (c.287T>C)?

AlphaMissense predicts likely benign (score 0.1987) — an in-silico prediction, not a clinical call.

ADA p.Val96Ala

Q: What condition is associated with ADA p.Val96Ala (c.287T>C)?

ADA p.Val96Ala (c.287T>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.287T>C · VCV3707192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

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	0.1987	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -10.46	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP 1.4, phastCons 0.007
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	16.64	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 0.00134% African / African-American · 1/74,852 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,904 alleles · very rare exomes 8/1,461,876 · genomes 2/152,028 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-Americangrpmax	0.00134%	74,852
European (non-Finnish)	0.000678%	147,500

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val96Ala
Coding: c.287T>C
MANE Select: NM_000022
Type: single nucleotide variant
Location: chr20:44626531 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 96: a β-strand

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.Val96Met Uncertain significance ★ ⚠ same residue
ADA p.Val96= 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-val96ala (accessed [today's date]).

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