Is CD3D c.406+5G>A pathogenic?

CD3D c.406+5G>A is classified Uncertain significance in CD3D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). Very rare (popmax 0.00771%, nfe); Associated with immunodeficiency 19.

What condition is associated with CD3D c.406+5G>A?

CD3D c.406+5G>A is associated with immunodeficiency 19 (ClinVar).

How common is CD3D c.406+5G>A in the general population?

CD3D c.406+5G>A is very rare (popmax 0.00771%, nfe) (gnomAD).

CD3D c.406+5G>A

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.

rs201527689 · VCV1402654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00771%, nfe)

Conditions

immunodeficiency 19

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +5	donor splice region (+5, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.75	donor loss, 5 bp away · masked 0 · deltas
Pangolin	Δ0.75	loss · gain 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 1.6, phastCons 1
Non-coding constraint	Z 0.62	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00771% European (non-Finnish) · 91/1,179,946 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.00576% 93/1,613,532 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00771%	12,966
Remaining individualsnot grpmax-eligible	0.0032%	31,237

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: CD3D
Coding: c.406+5G>A
MANE Select: NM_000732
dbSNP: rs201527689
Type: single nucleotide variant
Location: chr11:118339770 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 31 PDB

Full CD3D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 19 — 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

CD3D c.274+5G>A Pathogenic/Likely pathogenic ★★ same condition
CD3D c.407-2A>G Likely pathogenic ★★ same condition
CD3D p.Arg68Ter Pathogenic ★★ same condition
CD3D p.Cys93Ter Pathogenic ★★ same condition
CD3D c.274+4C>T Uncertain significance ★★ same condition
CD3D c.450+6C>T Uncertain significance ★★ same condition
CD3D p.Ala119Asp Uncertain significance ★★ ⚠ same condition
CD3D p.Arg169Gln 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/cd3d-c-406-plus-5g-a (accessed [today's date]).

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