Is CD3E p.Gly21= (c.63G>A) pathogenic?

CD3E p.Gly21= (c.63G>A) is classified Likely benign in CD3E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). Very rare (popmax 0.00223%, eas); Associated with immunodeficiency 18.

What condition is associated with CD3E p.Gly21= (c.63G>A)?

CD3E p.Gly21= (c.63G>A) is associated with immunodeficiency 18 (ClinVar).

How common is CD3E p.Gly21= (c.63G>A) in the general population?

CD3E p.Gly21= (c.63G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

CD3E p.Gly21=

Q: How is T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta inherited?

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

c.63G>A · rs200268620 · VCV2179376

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

immunodeficiency 18

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 -1.4	GERP -3.9
Overall
CADD	1.315	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,848 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000412% 6/1,454,716 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,848
Admixed American	0.00167%	59,930
European (non-Finnish)	0.00034%	293,722

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: CD3E
Protein: p.Gly21=
Coding: c.63G>A
MANE Select: NM_000733
dbSNP: rs200268620
Type: single nucleotide variant
Location: chr11:118307301 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.47 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.56 · 44 PDB

Full CD3E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CD3E c.103+1G>A Likely pathogenic ★★ same condition
CD3E c.49+1G>C Pathogenic ★★ same condition
CD3E p.Tyr96Ter Pathogenic/Likely pathogenic ★★ same condition
CD3E c.520+5G>A Uncertain significance ★★ same condition
CD3E p.Arg192Gln Uncertain significance ★★ ⚠ same condition
CD3E p.Arg206His Uncertain significance ★★ ⚠ same condition
CD3E p.Asn25Asp Uncertain significance ★★ ⚠ same condition
CD3E p.Asn74Thr 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/cd3e-p-gly21 (accessed [today's date]).

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