Is ADA p.Arg313Trp (c.937C>T) pathogenic?

ADA p.Arg313Trp (c.937C>T) is classified Uncertain significance in ADA (ClinVar, Expert panel, 2 submitters; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1879); Very rare (popmax 0.005%, amr); 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.Arg313Trp (c.937C>T) in the general population?

ADA p.Arg313Trp (c.937C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ADA p.Arg313Trp (c.937C>T)?

AlphaMissense predicts likely benign (score 0.1879) — an in-silico prediction, not a clinical call.

ADA p.Arg313Trp

Q: What condition is associated with ADA p.Arg313Trp (c.937C>T)?

ADA p.Arg313Trp (c.937C>T) 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.937C>T · rs79249850 · VCV1195941

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 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

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

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The c.937C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 313 (p.Arg313Trp). The filtering allele frequency (the upper threshold of the 95% CI of 25/1180022 alleles) of the c.937C>T variant in ADA is 0.00001454 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Another missense variant [c.938G>A, p.Arg313Gln] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met). To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting.

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

Computational evidence

Protein change
AlphaMissense	0.1879	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -13.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -0.54
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	20.9	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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00204% 33/1,614,128 alleles · very rare exomes 29/1,461,884 · genomes 4/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,251
East Asian	0.00223%	44,884
European (non-Finnish)	0.00212%	47,201
African / African-American	0.00133%	75,028
South Asian	0.0011%	91,080

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.Arg313Trp
Coding: c.937C>T
MANE Select: NM_000022
dbSNP: rs79249850
Type: single nucleotide variant
Location: chr20:44621056 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 313: 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 p.Arg313Gln Uncertain significance ★★★ ⚠ same residue
ADA p.Arg313= 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-arg313trp (accessed [today's date]).

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