Is CIC p.Arg2153Trp (c.6457C>T) pathogenic?

CIC p.Arg2153Trp (c.6457C>T) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1637); Very rare (popmax 0.00145%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Arg2153Trp (c.6457C>T)?

CIC p.Arg2153Trp (c.6457C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Arg2153Trp (c.6457C>T) in the general population?

CIC p.Arg2153Trp (c.6457C>T) is very rare (popmax 0.00145%, nfe) (gnomAD).

What do computational predictors say about CIC p.Arg2153Trp (c.6457C>T)?

AlphaMissense predicts likely benign (score 0.1637) — an in-silico prediction, not a clinical call.

CIC p.Arg2153Trp

c.6457C>T · rs587778201 · VCV133910

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1637	likely benign
REVEL	0.105	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 1.8	GERP 0.37, phastCons 1
Overall
CADD	25.6	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 R1244W vs ClinVar R2153W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00145% European (non-Finnish) · 17/1,172,616 alleles

Filtering AF 0.000883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000722%

Overall 0.00113% 18/1,596,136 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00145%	68,977
African / African-American	0.00134%	74,452

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.Arg2153Trp
Coding: c.6457C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs587778201
Type: single nucleotide variant
Location: chr19:42293216 (GRCh38)
Structure: AlphaFold pLDDT 75.09

Full CIC 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

CIC p.Arg2153Gln Likely benign ★ same residue
CIC c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp 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-arg2153trp (accessed [today's date]).

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