Is CIC p.Arg2222Trp (c.6664C>T) pathogenic?

CIC p.Arg2222Trp (c.6664C>T) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-02). AlphaMissense: likely benign (0.2293); Very rare (popmax 0.004%, afr).

How common is CIC p.Arg2222Trp (c.6664C>T) in the general population?

CIC p.Arg2222Trp (c.6664C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CIC p.Arg2222Trp (c.6664C>T)?

AlphaMissense predicts likely benign (score 0.2293) — an in-silico prediction, not a clinical call.

CIC p.Arg2222Trp

c.6664C>T · rs773220927 · VCV917625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2293	likely benign
REVEL	0.178	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1.8, phastCons 1
Overall
CADD	21.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1313W vs ClinVar R2222W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,946 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00105% 17/1,612,726 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,982
Admixed American	0.00167%	59,976
Remaining individualsnot grpmax-eligible	0.0016%	62,444
European (non-Finnish)	0.00102%	98,317

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: CIC
Protein: p.Arg2222Trp
Coding: c.6664C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs773220927
Type: single nucleotide variant
Location: chr19:42293733 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

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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/cic-p-arg2222trp (accessed [today's date]).

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