Is ADA p.Arg156His (c.467G>A) pathogenic?

ADA p.Arg156His (c.467G>A) is classified Pathogenic/Likely pathogenic in ADA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-10-03). AlphaMissense: ambiguous (0.5099); Very rare (popmax 0.00326%, nfe); Associated with severe combined immunodeficiency.

How common is ADA p.Arg156His (c.467G>A) in the general population?

ADA p.Arg156His (c.467G>A) is very rare (popmax 0.00326%, nfe) (gnomAD).

What do computational predictors say about ADA p.Arg156His (c.467G>A)?

AlphaMissense predicts ambiguous (score 0.5099) — an in-silico prediction, not a clinical call.

ADA p.Arg156His

Q: What condition is associated with ADA p.Arg156His (c.467G>A)?

ADA p.Arg156His (c.467G>A) is associated with severe combined immunodeficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (ClinVar).

c.467G>A · rs121908722 · VCV1984

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.5099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00326%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

severe combined immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.5099	ambiguous
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, 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 0.00326% European (non-Finnish) · 38/1,163,964 alleles

Filtering AF 0.00243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00213%

Overall 0.00247% 39/1,581,258 alleles · very rare exomes 38/1,429,110 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00326%	30,631
South Asian	0.00116%	86,552

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.Arg156His
Coding: c.467G>A
MANE Select: NM_000022
dbSNP: rs121908722
Type: single nucleotide variant
Location: chr20:44625580 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 156: a UniProt-annotated variant site (in adascid); a UniProt-annotated variant site (in adascid; loss of activity)

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

Disease context

severe combined immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ADA p.Arg156Cys Pathogenic ★★ same residue
ADA p.Arg156Leu Pathogenic ★ same residue
ADA p.Arg156Pro Likely pathogenic ★ same residue
ADA p.Arg156Ser 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

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-arg156his (accessed [today's date]).

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