Is CIITA p.Arg2Ser (c.4C>A) pathogenic?

CIITA p.Arg2Ser (c.4C>A) is classified Uncertain significance in CIITA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-15). AlphaMissense: ambiguous (0.5141); Absent from gnomAD v4.1; Associated with MHC class II deficiency.

What condition is associated with CIITA p.Arg2Ser (c.4C>A)?

CIITA p.Arg2Ser (c.4C>A) is associated with MHC class II deficiency (ClinVar).

How common is CIITA p.Arg2Ser (c.4C>A) in the general population?

CIITA p.Arg2Ser (c.4C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CIITA p.Arg2Ser (c.4C>A)?

AlphaMissense predicts ambiguous (score 0.5141) — an in-silico prediction, not a clinical call.

CIITA p.Arg2Ser

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.4C>A · rs375497479 · VCV965520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5141 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

MHC class II deficiency

Computational evidence

Protein change
AlphaMissense	0.5141	ambiguous
REVEL	0.219	benign-leaning
SaProt	LLR -4.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 6.2e-05 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CIITA
Protein: p.Arg2Ser
Coding: c.4C>A
MANE Select: NM_000246
dbSNP: rs375497479
Type: single nucleotide variant
Location: chr16:10877334 (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.Arg2His Uncertain significance ★★ ⚠ same residue
CIITA p.Arg2Cys Uncertain significance ★ 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-arg2ser (accessed [today's date]).

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