Is CD3D p.Gln140Lys (c.418C>A) pathogenic?

CD3D p.Gln140Lys (c.418C>A) is classified Uncertain significance in CD3D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-13). AlphaMissense: likely benign (0.1212); Rare (popmax 0.12%, eas); Associated with immunodeficiency 19.

What condition is associated with CD3D p.Gln140Lys (c.418C>A)?

CD3D p.Gln140Lys (c.418C>A) is associated with immunodeficiency 19 (ClinVar).

How common is CD3D p.Gln140Lys (c.418C>A) in the general population?

CD3D p.Gln140Lys (c.418C>A) is rare (popmax 0.12%, eas) (gnomAD).

What do computational predictors say about CD3D p.Gln140Lys (c.418C>A)?

AlphaMissense predicts likely benign (score 0.1212) — an in-silico prediction, not a clinical call.

CD3D p.Gln140Lys

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.418C>A · rs201126605 · VCV541673

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1212 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency 19

Computational evidence

Protein change
AlphaMissense	0.1212	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.74, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,442 bp · p 0.64 · regional, not allelic
Overall
CADD	22.1	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 0.12% East Asian · 54/44,878 alleles

Filtering AF 0.0946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00452% 73/1,614,104 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.12%	831
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.0117%	8,574
European (non-Finnish)	8.47e-05%	1,180,022

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.Gln140Lys
Coding: c.418C>A
MANE Select: NM_000732
dbSNP: rs201126605
Type: single nucleotide variant
Location: chr11:118339483 (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 140: 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 p.Gln140Glu Uncertain significance ★ ⚠ same residue
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

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-gln140lys (accessed [today's date]).

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