Is ADA p.Arg211Cys (c.631C>T) pathogenic?

ADA p.Arg211Cys (c.631C>T) is classified Likely pathogenic in ADA (ClinVar, Expert panel, 12 submitters; last evaluated 2024-01-10). AlphaMissense: likely benign (0.216); Ultra-rare (popmax 0.0517%, 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.Arg211Cys (c.631C>T) in the general population?

ADA p.Arg211Cys (c.631C>T) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about ADA p.Arg211Cys (c.631C>T)?

AlphaMissense predicts likely benign (score 0.216) — an in-silico prediction, not a clinical call.

ADA p.Arg211Cys

Q: What condition is associated with ADA p.Arg211Cys (c.631C>T)?

ADA p.Arg211Cys (c.631C>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.631C>T · rs121908740 · VCV1966

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.216 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

2/3 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):

PP1_Moderate PM3 PM5

Curation rationale (ClinGen, verbatim)

NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID: 2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate,PM3,PM5(VCEP specifications version 1).

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

Computational evidence

Protein change
AlphaMissense	0.216	likely benign ⚠ discordant with ClinVar
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -12.71	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	33.0	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 0.0517% Admixed American · 31/60,000 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00322% 52/1,613,970 alleles · ultra-rare exomes 51/1,461,770 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0517%	1,935
Remaining individualsnot grpmax-eligible	0.008%	12,495
European (non-Finnish)	0.00127%	78,665
South Asian	0.0011%	91,082

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.Arg211Cys
Coding: c.631C>T
MANE Select: NM_000022
dbSNP: rs121908740
Type: single nucleotide variant
Location: chr20:44623054 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 211: a UniProt-annotated variant site (in adascid; late onset; 4% of activity); a UniProt-annotated variant site (in adascid); a β-strand

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.Arg211His Pathogenic ★★★ same residue
ADA p.Arg211Ser Likely pathogenic ★ 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-arg211cys (accessed [today's date]).

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