Is CD3D p.Arg153Gln (c.458G>A) pathogenic?

CD3D p.Arg153Gln (c.458G>A) is classified Uncertain significance in CD3D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-14). AlphaMissense: likely benign (0.1023); Very rare (popmax 0.00446%, eas); Associated with immunodeficiency 19.

What condition is associated with CD3D p.Arg153Gln (c.458G>A)?

CD3D p.Arg153Gln (c.458G>A) is associated with immunodeficiency 19 (ClinVar).

How common is CD3D p.Arg153Gln (c.458G>A) in the general population?

CD3D p.Arg153Gln (c.458G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CD3D p.Arg153Gln (c.458G>A)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

CD3D p.Arg153Gln

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.458G>A · rs375444192 · VCV2152873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 19

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 0.86, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,442 bp · p 0.64 · regional, not allelic
Overall
CADD	22.0	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 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0026% 42/1,613,764 alleles · very rare exomes 39/1,461,702 · genomes 3/152,062 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
European (non-Finnish)	0.00305%	32,775
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,858
South Asian	0.0011%	91,052

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.Arg153Gln
Coding: c.458G>A
MANE Select: NM_000732
dbSNP: rs375444192
Type: single nucleotide variant
Location: chr11:118339220 (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 153: 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.Arg153Gly Uncertain significance ★ ⚠ same residue
CD3D p.Arg153Ter Conflicting classifications of pathogenicity ★ 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

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-arg153gln (accessed [today's date]).

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