Is CD8A c.403+4C>G pathogenic?

CD8A c.403+4C>G is classified Uncertain significance in CD8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-30). Very rare (popmax 0.00782%, nfe); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

How common is CD8A c.403+4C>G in the general population?

CD8A c.403+4C>G is very rare (popmax 0.00782%, nfe) (gnomAD).

CD8A c.403+4C>G

Q: What condition is associated with CD8A c.403+4C>G?

CD8A c.403+4C>G is associated with susceptibility to respiratory infections associated with CD8alpha chain mutation (ClinVar).

Q: How is Susceptibility to respiratory infections associated with CD8alpha chain mutation inherited?

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

rs368774730 · VCV639504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00782%, nfe)

Conditions

susceptibility to respiratory infections associated with CD8alpha chain mutation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -2.4
Overall
CADD	3.459	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00782% European (non-Finnish) · 92/1,176,842 alleles

Filtering AF 0.00649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00602%

Overall 0.00596% 96/1,610,254 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00782%	12,792
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0016%	62,354

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: CD8A
Coding: c.403+4C>G
MANE Select: NM_001768
dbSNP: rs368774730
Type: single nucleotide variant
Location: chr2:86790324 (GRCh38)
Gene constraint: LOEUF 1.496 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.03 · 8 PDB

Full CD8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

susceptibility to respiratory infections associated with CD8alpha chain mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Susceptibility to respiratory infections associated with CD8alpha chain mutation (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CD8A c.626-2A>T Uncertain significance ★★ same condition
CD8A p.Arg165Leu Uncertain significance ★★ ⚠ same condition
CD8A p.Arg165Pro Uncertain significance ★★ ⚠ same condition
CD8A p.His127Tyr Uncertain significance ★★ ⚠ same condition
CD8A p.His208Leu Uncertain significance ★★ ⚠ same condition
CD8A p.Leu10Arg Uncertain significance ★★ ⚠ same condition
CD8A p.Pro130Arg Uncertain significance ★★ ⚠ same condition
CD8A p.Pro130Leu 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/cd8a-c-403-plus-4c-g (accessed [today's date]).

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