What do computational predictors say about ADA p.Lys80Arg (c.239A>G)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

ADA p.Lys80Arg

Q: Is ADA p.Lys80Arg (c.239A>G) pathogenic?

ADA p.Lys80Arg (c.239A>G) is classified Benign in ADA (ClinVar, Expert panel, 13 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0757); Common (popmax 11.2%, mid) — 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.Lys80Arg (c.239A>G)?

ADA p.Lys80Arg (c.239A>G) 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.Lys80Arg (c.239A>G) in the general population?

ADA p.Lys80Arg (c.239A>G) is common (popmax 11.2%, mid) — 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.239A>G · rs11555566 · VCV1954

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 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

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_000022.4:c.239A>G variant in ADA is a missense variant predicted to cause substitution of lysine by arginine at amino acid 80 (p.Lys80Arg). The Popmax filtering allele frequency of this variant in the gnomAD v2.1.1 database is 0.06430, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 (BA1). This variant has been observed in 551 homozygous individuals with no feature of SCID, 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. (VCEP specifications version 1).

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

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	18.12	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 11.2% Middle Eastern · 673/6,030 alleles

Filtering AF 10.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 6% 96,874/1,614,086 alleles · common exomes 87,946/1,461,798 · genomes 8,928/152,288 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	11.2%	9
Ashkenazi Jewishnot grpmax-eligible	8.09%	12
African / African-American	6.76%	15
Remaining individualsnot grpmax-eligible	6.52%	15
European (non-Finnish)	6.2%	16
South Asian	5.91%	17
Admixed American	5.63%	18
Amishnot grpmax-eligible	5.37%	19
Finnishnot grpmax-eligible	4.1%	24
East Asian	0.0825%	1,212

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.Lys80Arg
Coding: c.239A>G
MANE Select: NM_000022
dbSNP: rs11555566
Type: single nucleotide variant
Location: chr20:44626579 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 80: a UniProt-annotated variant site (in); 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 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-lys80arg (accessed [today's date]).

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