Is CD3G p.Arg166= (c.496C>A) pathogenic?

CD3G p.Arg166= (c.496C>A) is classified Conflicting classifications of pathogenicity in CD3G (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 5.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to CD3gamma deficiency.

What condition is associated with CD3G p.Arg166= (c.496C>A)?

CD3G p.Arg166= (c.496C>A) is associated with combined immunodeficiency due to CD3gamma deficiency (ClinVar).

CD3G p.Arg166=

Q: How common is CD3G p.Arg166= (c.496C>A) in the general population?

CD3G p.Arg166= (c.496C>A) is common (popmax 5.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Combined immunodeficiency due to CD3gamma deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.496C>A · rs201529449 · VCV541655

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 5.6%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

combined immunodeficiency due to CD3gamma deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.1, phastCons 0.98
Overall
CADD	12.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.6% South Asian · 5,099/91,052 alleles

Filtering AF 5.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.42%

Overall 0.336% 5,418/1,613,836 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	5.6%	18
Remaining individualsnot grpmax-eligible	0.406%	246
Middle Eastern	0.247%	404
East Asian	0.0111%	8,977
African / African-American	0.0107%	9,374
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00297%	33,709

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: CD3G
Protein: p.Arg166=
Coding: c.496C>A
MANE Select: NM_000073
dbSNP: rs201529449
Type: single nucleotide variant
Location: chr11:118352416 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.05 · 38 PDB
Residue 166: an α-helix; the itam domain

Full CD3G gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to CD3gamma deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to CD3gamma deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CD3G p.Arg166Gln Uncertain significance ★★ ⚠ same residue
CD3G p.Arg166Ter Pathogenic ★ same residue
CD3G c.55+1G>T Likely pathogenic ★★ same condition
CD3G c.56-1G>A Likely pathogenic ★★ same condition
CD3G p.Lys69Ter Pathogenic ★★ same condition
CD3G p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
CD3G c.*308G>A Uncertain significance ★★ same condition
CD3G p.Arg146Thr Uncertain significance ★★ ⚠ 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/cd3g-p-arg166 (accessed [today's date]).

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