Is CIC p.Arg2114Trp (c.6340C>T) pathogenic?

CIC p.Arg2114Trp (c.6340C>T) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1491); Very rare (popmax 0.0067%, eas); Associated with CIC-related disorder.

What condition is associated with CIC p.Arg2114Trp (c.6340C>T)?

CIC p.Arg2114Trp (c.6340C>T) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Arg2114Trp (c.6340C>T) in the general population?

CIC p.Arg2114Trp (c.6340C>T) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about CIC p.Arg2114Trp (c.6340C>T)?

AlphaMissense predicts likely benign (score 0.1491) — an in-silico prediction, not a clinical call.

CIC p.Arg2114Trp

c.6340C>T · rs540906276 · VCV929080

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.1491	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.5, phastCons 1
Overall
CADD	26.0	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 R1205W vs ClinVar R2114W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0067% East Asian · 3/44,758 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00106% 17/1,609,816 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,919
South Asian	0.00551%	18,156
Admixed American	0.00168%	59,500
Remaining individualsnot grpmax-eligible	0.00161%	62,244
European (non-Finnish)	0.000594%	168,401

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.Arg2114Trp
Coding: c.6340C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs540906276
Type: single nucleotide variant
Location: chr19:42293099 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

CIC-related disorder

Similar variants

CIC p.Asn1136Ser Likely pathogenic ★★ same condition
SLC25A1 p.Ala274Val Pathogenic/Likely pathogenic ★★ same condition
SLC25A1 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
CIC p.Arg800His Uncertain significance ★★ same condition
CIC p.Gly17Val Uncertain significance ★★ same condition
CIC p.Val989Ala Uncertain significance ★★ ⚠ same condition
CIC p.Arg800Cys Likely pathogenic ★ same condition
CIC c.7186+3G>T 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/cic-p-arg2114trp (accessed [today's date]).

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