Is CD3G p.Arg166Gln (c.497G>A) pathogenic?

CD3G p.Arg166Gln (c.497G>A) is classified Uncertain significance in CD3G (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-20). AlphaMissense: likely benign (0.227); Very rare (popmax 0.00636%, nfe); Associated with combined immunodeficiency due to CD3gamma deficiency.

What condition is associated with CD3G p.Arg166Gln (c.497G>A)?

CD3G p.Arg166Gln (c.497G>A) is associated with combined immunodeficiency due to CD3gamma deficiency (ClinVar).

How common is CD3G p.Arg166Gln (c.497G>A) in the general population?

CD3G p.Arg166Gln (c.497G>A) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about CD3G p.Arg166Gln (c.497G>A)?

AlphaMissense predicts likely benign (score 0.227) — an in-silico prediction, not a clinical call.

CD3G p.Arg166Gln

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.497G>A · rs764084817 · VCV1430850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.227 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined immunodeficiency due to CD3gamma deficiency

Computational evidence

Protein change
AlphaMissense	0.227	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,042 bp · p 0.94 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,179,940 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00483% 78/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,733
Admixed American	0.00167%	59,994
African / African-American	0.00134%	74,874
South Asian	0.0011%	91,074

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.Arg166Gln
Coding: c.497G>A
MANE Select: NM_000073
dbSNP: rs764084817
Type: single nucleotide variant
Location: chr11:118352417 (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.Arg166Ter Pathogenic ★ same residue
CD3G p.Arg166= Conflicting classifications of pathogenicity ★ 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-arg166gln (accessed [today's date]).

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