Is CIITA p.Ala648= (c.1944A>T) pathogenic?

CIITA p.Ala648= (c.1944A>T) is classified Conflicting classifications of pathogenicity in CIITA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0101%, nfe); Associated with MHC class II deficiency.

What condition is associated with CIITA p.Ala648= (c.1944A>T)?

CIITA p.Ala648= (c.1944A>T) is associated with MHC class II deficiency (ClinVar).

How common is CIITA p.Ala648= (c.1944A>T) in the general population?

CIITA p.Ala648= (c.1944A>T) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

CIITA p.Ala648=

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.1944A>T · rs778678693 · VCV884506

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Conditions

MHC class II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -4.1
Overall
CADD	0.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% European (non-Finnish) · 119/1,179,776 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00781% 126/1,612,726 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,914
Remaining individualsnot grpmax-eligible	0.00641%	15,612
Admixed American	0.005%	19,989

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.Ala648=
Coding: c.1944A>T
MANE Select: NM_000246
dbSNP: rs778678693
Type: single nucleotide variant
Location: chr16:10907436 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.10
Residue 648: the nacht domain

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-ala648 (accessed [today's date]).

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