Is CD3D p.Thr139Ile (c.416C>T) pathogenic?

CD3D p.Thr139Ile (c.416C>T) is classified Uncertain significance in CD3D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1459); Ultra-rare (popmax 0.0169%, nfe); Associated with immunodeficiency 19.

What condition is associated with CD3D p.Thr139Ile (c.416C>T)?

CD3D p.Thr139Ile (c.416C>T) is associated with immunodeficiency 19 (ClinVar).

How common is CD3D p.Thr139Ile (c.416C>T) in the general population?

CD3D p.Thr139Ile (c.416C>T) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about CD3D p.Thr139Ile (c.416C>T)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

CD3D p.Thr139Ile

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.416C>T · rs527584796 · VCV420806

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 19

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.62, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 3,442 bp · p 0.64 · regional, not allelic
Overall
CADD	11.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% European (non-Finnish) · 200/1,180,010 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0131% 211/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,900
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Finnishnot grpmax-eligible	0.00469%	21,345
Admixed American	0.00167%	60,022
African / African-American	0.00133%	75,002

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
Protein: p.Thr139Ile
Coding: c.416C>T
MANE Select: NM_000732
dbSNP: rs527584796
Type: single nucleotide variant
Location: chr11:118339485 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.57 · 31 PDB
Residue 139: the itam domain

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-p-thr139ile (accessed [today's date]).

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