Is CIITA p.Arg409Gln (c.1226G>A) pathogenic?

CIITA p.Arg409Gln (c.1226G>A) is classified Uncertain significance in CIITA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-11). AlphaMissense: likely benign (0.075); Very rare (popmax 0.00534%, afr); Associated with MHC class II deficiency.

What condition is associated with CIITA p.Arg409Gln (c.1226G>A)?

CIITA p.Arg409Gln (c.1226G>A) is associated with MHC class II deficiency (ClinVar).

How common is CIITA p.Arg409Gln (c.1226G>A) in the general population?

CIITA p.Arg409Gln (c.1226G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CIITA p.Arg409Gln (c.1226G>A)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

CIITA p.Arg409Gln

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.1226G>A · rs745358587 · VCV1398804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MHC class II deficiency

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP -4.3
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 6.2e-05 · regional, not allelic
Overall
CADD	11.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00534% African / African-American · 4/74,940 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00242% 39/1,611,326 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.85%	35
African / African-Americangrpmax	0.00534%	18,735
Remaining individualsnot grpmax-eligible	0.0032%	31,237
South Asian	0.0022%	45,529
Finnishnot grpmax-eligible	0.00163%	61,472
European (non-Finnish)	0.000339%	294,978

Amish 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: CIITA
Protein: p.Arg409Gln
Coding: c.1226G>A
MANE Select: NM_000246
dbSNP: rs745358587
Type: single nucleotide variant
Location: chr16:10906718 (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 p.Arg409Trp Uncertain significance ★★ ⚠ same residue
CIITA p.Arg409= Likely benign ★ same residue
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

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-arg409gln (accessed [today's date]).

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