Is CD3G p.Leu174Pro (c.521T>C) pathogenic?

CD3G p.Leu174Pro (c.521T>C) is classified Uncertain significance in CD3G (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). AlphaMissense: likely pathogenic (0.8594); Very rare (popmax 0.00314%, nfe); Associated with combined immunodeficiency due to CD3gamma deficiency.

What condition is associated with CD3G p.Leu174Pro (c.521T>C)?

CD3G p.Leu174Pro (c.521T>C) is associated with combined immunodeficiency due to CD3gamma deficiency (ClinVar).

How common is CD3G p.Leu174Pro (c.521T>C) in the general population?

CD3G p.Leu174Pro (c.521T>C) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about CD3G p.Leu174Pro (c.521T>C)?

AlphaMissense predicts likely pathogenic (score 0.8594) — an in-silico prediction, not a clinical call.

CD3G p.Leu174Pro

Q: How is Combined immunodeficiency due to CD3gamma deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.521T>C · rs200685479 · VCV1056865

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined immunodeficiency due to CD3gamma deficiency

Computational evidence

Protein change
AlphaMissense	0.8594	likely pathogenic · top 8% in CD3G
REVEL	0.568	indeterminate
SaProt	LLR -10.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,042 bp · p 0.94 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00314% European (non-Finnish) · 37/1,179,992 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00254% 41/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)grpmax	0.00314%	31,892

Remaining individuals 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: CD3G
Protein: p.Leu174Pro
Coding: c.521T>C
MANE Select: NM_000073
dbSNP: rs200685479
Type: single nucleotide variant
Location: chr11:118352441 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.05 · 38 PDB
Residue 174: the itam domain

Full CD3G gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to CD3gamma deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to CD3gamma deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CD3G c.55+1G>T Likely pathogenic ★★ same condition
CD3G c.56-1G>A Likely pathogenic ★★ same condition
CD3G p.Lys69Ter Pathogenic ★★ same condition
CD3G p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
CD3G c.*308G>A Uncertain significance ★★ same condition
CD3G p.Arg146Thr Uncertain significance ★★ ⚠ same condition
CD3G p.Arg166Gln Uncertain significance ★★ ⚠ same condition
CD3G p.Asn156Ser 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/cd3g-p-leu174pro (accessed [today's date]).

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