Is CD3E p.Pro35Ser (c.103C>T) pathogenic?

CD3E p.Pro35Ser (c.103C>T) is classified Benign/Likely benign in CD3E (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-05). AlphaMissense: likely benign (0.1224); Rare (popmax 0.18%, nfe); Associated with immunodeficiency 18.

What condition is associated with CD3E p.Pro35Ser (c.103C>T)?

CD3E p.Pro35Ser (c.103C>T) is associated with immunodeficiency 18 (ClinVar).

How common is CD3E p.Pro35Ser (c.103C>T) in the general population?

CD3E p.Pro35Ser (c.103C>T) is rare (popmax 0.18%, nfe) (gnomAD).

What do computational predictors say about CD3E p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.1224) — an in-silico prediction, not a clinical call.

CD3E p.Pro35Ser

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.103C>T · rs143949187 · VCV302661

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1224 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 18

Computational evidence

Protein change
AlphaMissense	0.1224	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.7	GERP -3.9
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.052 · regional, not allelic
Overall
CADD	0.012	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 0.18% European (non-Finnish) · 2,115/1,177,500 alleles

Filtering AF 0.173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.199% 3,206/1,611,270 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.37%	73
Ashkenazi Jewishnot grpmax-eligible	0.318%	315
European (non-Finnish)grpmax	0.18%	557
Remaining individualsnot grpmax-eligible	0.141%	709
Middle Eastern	0.033%	3,026
Admixed American	0.0267%	3,751
East Asian	0.0134%	7,477
African / African-American	0.012%	8,328
South Asian	0.0022%	45,507

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro35Ser
Coding: c.103C>T
MANE Select: NM_000733
dbSNP: rs143949187
Type: single nucleotide variant
Location: chr11:118312170 (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 35: an α-helix; the ig-like domain

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 p.Pro35= Likely benign ★ same residue
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

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-pro35ser (accessed [today's date]).

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