What do computational predictors say about ADA p.Asp8Asn (c.22G>A)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

ADA p.Asp8Asn

Q: Is ADA p.Asp8Asn (c.22G>A) pathogenic?

ADA p.Asp8Asn (c.22G>A) is classified Benign in ADA (ClinVar, Expert panel, 13 submitters; last evaluated 2023-10-10). AlphaMissense: likely benign (0.0934); Common (popmax 13%, sas) — too common for a highly-penetrant pathogenic allele; Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

Q: What condition is associated with ADA p.Asp8Asn (c.22G>A)?

ADA p.Asp8Asn (c.22G>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 common is ADA p.Asp8Asn (c.22G>A) in the general population?

ADA p.Asp8Asn (c.22G>A) is common (popmax 13%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.22G>A · rs73598374 · VCV1973

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

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

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

BS2_Supporting BA1

Curation rationale (ClinGen, verbatim)

The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0).

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

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.1	GERP -2.5, phastCons 0.72
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	14.93	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 13% South Asian · 10,988/84,708 alleles

Filtering AF 12.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.7%

Overall 5.61% 86,445/1,540,646 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	13%	8
Middle Eastern	11.7%	9
Ashkenazi Jewishnot grpmax-eligible	9.36%	11
Amishnot grpmax-eligible	7.13%	14
Finnishnot grpmax-eligible	6.56%	15
Remaining individualsnot grpmax-eligible	6.34%	16
European (non-Finnish)	5.34%	19
East Asian	4.19%	24
Admixed American	2.87%	35
African / African-American	0.989%	101

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.Asp8Asn
Coding: c.22G>A
MANE Select: NM_000022
dbSNP: rs73598374
Type: single nucleotide variant
Location: chr20:44651586 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 8: a UniProt-annotated variant site (allele ada*2; found in about 10% of the population; affects duration and intensity of deep sleep; enhances negative effects of sleep loss during sleep deprivation; may have a protective role against male infertility; 20% to 30% decrease in activity)

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)

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ADA c.606+1G>T Likely pathogenic ★★★ same condition
ADA c.975+1G>A Pathogenic ★★★ same condition
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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-asp8asn (accessed [today's date]).

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