Is CD3E c.352+20C>G pathogenic?

CD3E c.352+20C>G is classified Likely benign in CD3E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-30). Very rare (popmax 0.0011%, sas); Associated with immunodeficiency 18.

What condition is associated with CD3E c.352+20C>G?

CD3E c.352+20C>G is associated with immunodeficiency 18 (ClinVar).

How common is CD3E c.352+20C>G in the general population?

CD3E c.352+20C>G is very rare (popmax 0.0011%, sas) (gnomAD).

CD3E c.352+20C>G

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.

VCV3675955

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

immunodeficiency 18

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +20	near-intronic (+20 nt from the splice site)
SpliceAI	Δ0.38	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.47	GERP -2.8, phastCons 0.001
Non-coding constraint	Z 3.13	1 kb window · o/e 0.77 · regional · uncalibrated
Overall
CADD	1.375	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,050 alleles

Overall 0.000137% 2/1,461,732 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asiangrpmax	0.0011%	91,050

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.352+20C>G
MANE Select: NM_000733
Type: single nucleotide variant
Location: chr11:118312886 (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-c-352-plus-20c-g (accessed [today's date]).

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