Is CD3E p.Val19Ile (c.55G>A) pathogenic?

CD3E p.Val19Ile (c.55G>A) is classified Conflicting classifications of pathogenicity in CD3E (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-24). AlphaMissense: likely benign (0.0861); Rare (popmax 0.149%, mid); Associated with immunodeficiency 18.

What condition is associated with CD3E p.Val19Ile (c.55G>A)?

CD3E p.Val19Ile (c.55G>A) is associated with immunodeficiency 18 (ClinVar).

How common is CD3E p.Val19Ile (c.55G>A) in the general population?

CD3E p.Val19Ile (c.55G>A) is rare (popmax 0.149%, mid) (gnomAD).

What do computational predictors say about CD3E p.Val19Ile (c.55G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

CD3E p.Val19Ile

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.55G>A · rs143630318 · VCV426577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 18

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 15 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.97	GERP -3.9
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.052 · regional, not allelic
Overall
CADD	6.531	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 0.149% Middle Eastern · 9/6,050 alleles

Filtering AF 0.0775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00237% 38/1,606,640 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	672
Remaining individualsnot grpmax-eligible	0.00803%	12,457
African / African-American	0.00267%	37,448
South Asian	0.00221%	45,349
European (non-Finnish)	0.0017%	58,714

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.Val19Ile
Coding: c.55G>A
MANE Select: NM_000733
dbSNP: rs143630318
Type: single nucleotide variant
Location: chr11:118307293 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.47 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.56 · 44 PDB

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 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-val19ile (accessed [today's date]).

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