Is ADA p.Pro104Leu (c.311C>T) pathogenic?

ADA p.Pro104Leu (c.311C>T) is classified Likely pathogenic in ADA (ClinVar, Expert panel, 5 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.8995); Very rare (popmax 0.00329%, sas); 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.Pro104Leu (c.311C>T) in the general population?

ADA p.Pro104Leu (c.311C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ADA p.Pro104Leu (c.311C>T)?

AlphaMissense predicts likely pathogenic (score 0.8995) — an in-silico prediction, not a clinical call.

ADA p.Pro104Leu

Q: What condition is associated with ADA p.Pro104Leu (c.311C>T)?

ADA p.Pro104Leu (c.311C>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 (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.311C>T · rs1452483770 · VCV565486

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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

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

PP4_Moderate PM3_Supporting PM2_Supporting PS3_Moderate

Curation rationale (ClinGen, verbatim)

The variant NM_000022.4(ADA):c.311C>T is a missense variant predicted to cause a proline to leucine substitution at amino acid residue 104. The variant has been identified in at least two homozygous patients with SCID due to adenosine deaminase deficiency (PMID: 7691348, 9758612) (0.25pt each for PM3, total 1pt, PM3_supporting). At least one of those patients met diagnostic criteria for ADA-SCID (0.5pt) and displayed less than 1% ADA enzymatic activity in patient cells (5pt) (total 5.5pt, PP4_moderate). Additionally, the variant showed less than 0.05% ADA enzymatic activity compared to wild type (group 1), when expressed into E. Coli (PS3_moderate). Finally, the variant has a popmax filtering allele frequency of 0.00001082 based on the South Asian population in gnomAD, which is lower than the 0.0001742 cutoff established by the SCID VCEP for PM2_supporting. In summary, this variant meets criteria to be classified as likely pathogenic for adenosine deaminase deficiency based on the ACMG criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting, PM3_supporting, PP4_moderate, and PS3_moderate (VCEP specifications version 2.1.0).

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

Computational evidence

Protein change
AlphaMissense	0.8995	likely pathogenic ✓ concordant with ClinVar
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -16.34	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 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	32.0	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 0.00329% South Asian · 3/91,074 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00041% 6/1,461,834 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,358
European (non-Finnish)	0.000254%	393,342

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.Pro104Leu
Coding: c.311C>T
MANE Select: NM_000022
dbSNP: rs1452483770
Type: single nucleotide variant
Location: chr20:44626507 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 104: 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

Also linked: severe combined immunodeficiency

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.Pro104= 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
ADA p.Ala329Val 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-pro104leu (accessed [today's date]).

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