Is CD3E p.Ile133Thr (c.398T>C) pathogenic?

CD3E p.Ile133Thr (c.398T>C) is classified Uncertain significance in CD3E (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-11). AlphaMissense: likely benign (0.298); Ultra-rare (popmax 0.0413%, afr); Associated with Inborn genetic diseases.

What condition is associated with CD3E p.Ile133Thr (c.398T>C)?

CD3E p.Ile133Thr (c.398T>C) is associated with Inborn genetic diseases, immunodeficiency 18 (ClinVar).

How common is CD3E p.Ile133Thr (c.398T>C) in the general population?

CD3E p.Ile133Thr (c.398T>C) is ultra-rare (popmax 0.0413%, afr) (gnomAD).

What do computational predictors say about CD3E p.Ile133Thr (c.398T>C)?

AlphaMissense predicts likely benign (score 0.298) — an in-silico prediction, not a clinical call.

CD3E p.Ile133Thr

c.398T>C · rs200987721 · VCV951896

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.298 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.298	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 0.98
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.052 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0413% African / African-American · 31/75,014 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00279% 45/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0413%	2,420
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.005%	20,009
European (non-Finnish)	0.000593%	168,553

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.Ile133Thr
Coding: c.398T>C
MANE Select: NM_000733
dbSNP: rs200987721
Type: single nucleotide variant
Location: chr11:118313752 (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 133: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 18

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-ile133thr (accessed [today's date]).

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