Is CD3E p.Gly18= (c.54C>T) pathogenic?

CD3E p.Gly18= (c.54C>T) is classified Benign in CD3E (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 47.5%, amr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 18.

What condition is associated with CD3E p.Gly18= (c.54C>T)?

CD3E p.Gly18= (c.54C>T) is associated with immunodeficiency 18 (ClinVar).

CD3E p.Gly18=

Q: How common is CD3E p.Gly18= (c.54C>T) in the general population?

CD3E p.Gly18= (c.54C>T) is common (popmax 47.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.54C>T · rs1126924 · VCV302659

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 47.5%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency 18

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.6	GERP -4
Overall
CADD	5.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 47.5% Admixed American · 28,374/59,710 alleles

Filtering AF 47.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 46.9%

Overall 30.5% 485,755/1,593,588 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	47.5%	2
Amishnot grpmax-eligible	37%	3
Finnishnot grpmax-eligible	33.1%	3
European (non-Finnish)	31.4%	3
South Asian	30.7%	3
Middle Eastern	30.5%	3
Ashkenazi Jewishnot grpmax-eligible	29.7%	3
Remaining individualsnot grpmax-eligible	29.7%	3
East Asian	20.3%	5
African / African-American	7.69%	13

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.Gly18=
Coding: c.54C>T
MANE Select: NM_000733
dbSNP: rs1126924
Type: single nucleotide variant
Location: chr11:118307292 (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-gly18 (accessed [today's date]).

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