Is CIITA p.Arg669Cys (c.2005C>T) pathogenic?

CIITA p.Arg669Cys (c.2005C>T) is classified Uncertain significance in CIITA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.15); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with CIITA p.Arg669Cys (c.2005C>T)?

CIITA p.Arg669Cys (c.2005C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CIITA p.Arg669Cys (c.2005C>T) in the general population?

CIITA p.Arg669Cys (c.2005C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CIITA p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely benign (score 0.15) — an in-silico prediction, not a clinical call.

CIITA p.Arg669Cys

c.2005C>T · VCV4228939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.15 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.15	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 6.2e-05 · regional, not allelic
Overall
CADD	26.3	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 0.0107% African / African-American · 8/74,904 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000744% 12/1,613,736 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,363
European (non-Finnish)	0.000339%	294,998

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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_000246
Type: single nucleotide variant
Location: chr16:10907497 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.10
Residue 669: the nacht domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIITA p.Arg669His Uncertain significance ★★ ⚠ same residue
CIITA p.Ala291Val Uncertain significance ★★ ⚠ same condition
CIITA p.Ala383Asp Uncertain significance ★★ ⚠ same condition
CIITA p.Ala689Val Uncertain significance ★★ ⚠ same condition
CIITA p.Ala767Thr Uncertain significance ★★ ⚠ same condition
CIITA p.Ala813Thr Uncertain significance ★★ ⚠ same condition
CIITA p.Arg369Ser Uncertain significance ★★ ⚠ same condition
CIITA p.Arg390Trp 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/ciita-p-arg669cys (accessed [today's date]).

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