Is CD3E p.Gly194Ser (c.580G>A) pathogenic?

CD3E p.Gly194Ser (c.580G>A) is classified Uncertain significance in CD3E (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.504); Ultra-rare (popmax 0.0457%, nfe); Associated with immunodeficiency 18.

What condition is associated with CD3E p.Gly194Ser (c.580G>A)?

CD3E p.Gly194Ser (c.580G>A) is associated with immunodeficiency 18 (ClinVar).

How common is CD3E p.Gly194Ser (c.580G>A) in the general population?

CD3E p.Gly194Ser (c.580G>A) is ultra-rare (popmax 0.0457%, nfe) (gnomAD).

What do computational predictors say about CD3E p.Gly194Ser (c.580G>A)?

AlphaMissense predicts ambiguous (score 0.504) — an in-silico prediction, not a clinical call.

CD3E p.Gly194Ser

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.580G>A · rs141553540 · VCV302664

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.504 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0457%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

immunodeficiency 18

Computational evidence

Protein change
AlphaMissense	0.504	ambiguous
REVEL	0.278	benign-leaning
SaProt	LLR -6.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.052 · regional, not allelic
Overall
CADD	28.6	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 0.0457% European (non-Finnish) · 539/1,179,850 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.0342% 552/1,613,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0457%	2,189
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00936%	10,679

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.Gly194Ser
Coding: c.580G>A
MANE Select: NM_000733
dbSNP: rs141553540
Type: single nucleotide variant
Location: chr11:118315498 (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 194: an α-helix; the itam domain; the 'disordered' region

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-gly194ser (accessed [today's date]).

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