Is ADA p.Asp123fs (c.366_367del) pathogenic?

ADA p.Asp123fs (c.366367del) is classified Pathogenic/Likely pathogenic in ADA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-14). Very rare (popmax 0.00539%, nfe); Associated with ADA-related disorder.

How common is ADA p.Asp123fs (c.366_367del) in the general population?

ADA p.Asp123fs (c.366_367del) is very rare (popmax 0.00539%, nfe) (gnomAD).

ADA p.Asp123fs

Q: What condition is associated with ADA p.Asp123fs (c.366_367del)?

ADA p.Asp123fs (c.366_367del) is associated with ADA-related disorder, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, severe combined immunodeficiency (ClinVar).

c.366_367del · rs758073965 · VCV1074979

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00539%, nfe)

Conditions

ADA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00539% European (non-Finnish) · 62/1,151,340 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00389%

Overall 0.00417% 65/1,559,816 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00539%	18,570
Remaining individualsnot grpmax-eligible	0.00331%	30,211
African / African-American	0.00136%	73,494

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.Asp123fs
Coding: c.366_367del
MANE Select: NM_000022
dbSNP: rs758073965
Type: Deletion
Location: chr20:44625680 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB

Full ADA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ADA-related disorder

Also linked: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency severe combined immunodeficiency

Similar variants

ADA p.Asp123Asn Uncertain significance ★★ ⚠ same residue
ADA p.Asp123Ala Uncertain significance ★ ⚠ same residue
ADA p.Val177_Val178insTer Pathogenic ★★★ same condition
ADA c.976-1_979del Pathogenic/Likely pathogenic ★★ same condition
ADA p.Arg324fs Pathogenic ★★ same condition
ADA p.Glu319fs Pathogenic ★★ same condition
ADA p.Gly136fs Likely pathogenic ★★ same condition
ADA p.Leu137fs 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-asp123fs (accessed [today's date]).

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