Is CD3E p.Lys177fs (c.530del) pathogenic?

CD3E p.Lys177fs (c.530del) is classified Uncertain significance in CD3E (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-03). Ultra-rare (popmax 0.02%, amr); Associated with immunodeficiency 18.

What condition is associated with CD3E p.Lys177fs (c.530del)?

CD3E p.Lys177fs (c.530del) is associated with immunodeficiency 18 (ClinVar).

How common is CD3E p.Lys177fs (c.530del) in the general population?

CD3E p.Lys177fs (c.530del) is ultra-rare (popmax 0.02%, amr) (gnomAD).

CD3E p.Lys177fs

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.530del · rs745496161 · VCV855359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

immunodeficiency 18

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (8 of 9, 38 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.36	GERP -3.3, phastCons 0.99
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/59,998 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000744% 12/1,613,814 alleles · ultra-rare

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.Lys177fs
Coding: c.530del
MANE Select: NM_000733
dbSNP: rs745496161
Type: Deletion
Location: chr11:118314456 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.47 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.56 · 44 PDB
Residue 177: the 'disordered' region; the 'numb-binding region' region

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 p.Gly143fs Pathogenic ★ same condition
CD3E p.Ser88fs Pathogenic ★ same condition
CD3E p.Gly68_Gly76del Uncertain significance ★ same condition
CD3E c.353-5del Benign ★ same condition
CD3E c.50-10del Likely benign ★ same condition
CD3E c.521-15del Benign ★ same condition
CD3E c.568-11_568-10del Likely benign ★ same condition
CD3E c.103+1G>A Likely pathogenic ★★ 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-lys177fs (accessed [today's date]).

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