Is CIT p.Arg1394Cys (c.4180C>T) pathogenic?

CIT p.Arg1394Cys (c.4180C>T) is classified Uncertain significance in CIT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: ambiguous (0.3738); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with CIT p.Arg1394Cys (c.4180C>T)?

CIT p.Arg1394Cys (c.4180C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CIT p.Arg1394Cys (c.4180C>T) in the general population?

CIT p.Arg1394Cys (c.4180C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CIT p.Arg1394Cys (c.4180C>T)?

AlphaMissense predicts ambiguous (score 0.3738) — an in-silico prediction, not a clinical call.

CIT p.Arg1394Cys

c.4180C>T · VCV3833591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3738	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -9.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 32 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1352C vs ClinVar R1394C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,880 alleles

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

Overall 0.00062% 10/1,613,728 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,720
South Asian	0.0022%	45,506
Admixed American	0.00167%	59,958
European (non-Finnish)	0.000254%	393,309

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: CIT
Protein: p.Arg1394Cys
Coding: c.4180C>T
MANE Select: NM_001206999
Type: single nucleotide variant
Location: chr12:119714323 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.75

Full CIT 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

CIT p.Arg1178Ter Pathogenic ★★ same condition
CIT c.4168+5G>A Uncertain significance ★★ same condition
CIT p.Ala1527Val Uncertain significance ★★ ⚠ same condition
CIT p.Ala495Ser Uncertain significance ★★ ⚠ same condition
CIT p.Ala8Val Uncertain significance ★★ ⚠ same condition
CIT p.Arg100Gly Uncertain significance ★★ ⚠ same condition
CIT p.Arg1469Cys Uncertain significance ★★ ⚠ same condition
CIT p.Arg1861Cys 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/cit-p-arg1394cys (accessed [today's date]).

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