Is CIITA p.Cys75= (c.225C>T) pathogenic?

CIITA p.Cys75= (c.225C>T) is classified Benign in CIITA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with MHC class II deficiency.

What condition is associated with CIITA p.Cys75= (c.225C>T)?

CIITA p.Cys75= (c.225C>T) is associated with MHC class II deficiency (ClinVar).

CIITA p.Cys75=

Q: How common is CIITA p.Cys75= (c.225C>T) in the general population?

CIITA p.Cys75= (c.225C>T) is common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Immunodeficiency by defective expression of MHC class II inherited?

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

c.225C>T · rs2229318 · VCV317677

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 10.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

MHC class II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.5	GERP -4
Overall
CADD	0.236	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.8% African / African-American · 8,108/74,974 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 0.567% 9,147/1,614,074 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.8%	9
Remaining individualsnot grpmax-eligible	0.75%	133
Admixed American	0.665%	150
Middle Eastern	0.412%	242
South Asian	0.0582%	1,718
East Asian	0.0156%	6,412
European (non-Finnish)	0.00729%	13,721

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: CIITA
Protein: p.Cys75=
Coding: c.225C>T
MANE Select: NM_000246
dbSNP: rs2229318
Type: single nucleotide variant
Location: chr16:10895694 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.10

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

Disease context

MHC class II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency by defective expression of MHC class II (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CIITA c.199+1G>A Likely pathogenic ★★ same condition
CIITA c.2888+1G>A Pathogenic/Likely pathogenic ★★ same condition
CIITA c.2889-1G>T Pathogenic/Likely pathogenic ★★ same condition
CIITA c.436+1G>A Likely pathogenic ★★ same condition
CIITA c.628+1G>A Likely pathogenic ★★ same condition
CIITA p.Arg308Ter Pathogenic/Likely pathogenic ★★ same condition
CIITA p.Arg539Ter Pathogenic/Likely pathogenic ★★ same condition
CIITA p.Gln228Ter Pathogenic ★★ 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/ciita-p-cys75 (accessed [today's date]).

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