Is CIC p.Arg1401Trp (c.4201C>T) pathogenic?

CIC p.Arg1401Trp (c.4201C>T) is classified Pathogenic in CIC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2010-12-01). AlphaMissense: ambiguous (0.3537); Very rare (popmax 0.00333%, amr); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Arg1401Trp (c.4201C>T)?

CIC p.Arg1401Trp (c.4201C>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Arg1401Trp (c.4201C>T) in the general population?

CIC p.Arg1401Trp (c.4201C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CIC p.Arg1401Trp (c.4201C>T)?

AlphaMissense predicts ambiguous (score 0.3537) — an in-silico prediction, not a clinical call.

CIC p.Arg1401Trp

c.4201C>T · rs373584239 · VCV437890

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.3537	ambiguous
REVEL	0.351	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.54, phastCons 1
Overall
CADD	25.7	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 R492W vs ClinVar R1401W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,996 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,998
European (non-Finnish)	0.000169%	589,984

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.Arg1401Trp
Coding: c.4201C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs373584239
Type: single nucleotide variant
Location: chr19:42290242 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC p.Arg1401Gln Uncertain significance ★ ⚠ same residue
CIC p.Arg1401Gly Uncertain significance ★ same residue
CIC p.Arg1401Pro Uncertain significance ★ same residue
CIC p.Arg1401= Likely benign ★ same residue
CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ 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-arg1401trp (accessed [today's date]).

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