Is CIC p.Pro1834Leu (c.5501C>T) pathogenic?

CIC p.Pro1834Leu (c.5501C>T) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-10). AlphaMissense: likely pathogenic (0.8547); Very rare (popmax 8.47e-05%, nfe); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Pro1834Leu (c.5501C>T)?

CIC p.Pro1834Leu (c.5501C>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Pro1834Leu (c.5501C>T) in the general population?

CIC p.Pro1834Leu (c.5501C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CIC p.Pro1834Leu (c.5501C>T)?

AlphaMissense predicts likely pathogenic (score 0.8547) — an in-silico prediction, not a clinical call.

CIC p.Pro1834Leu

c.5501C>T · rs2147280018 · VCV2429946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.8547	likely pathogenic
REVEL	0.354	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Overall
CADD	25.4	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 P925L vs ClinVar P1834L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.85e-05% 1/1,460,716 alleles · very rare

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.Pro1834Leu
Coding: c.5501C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs2147280018
Type: single nucleotide variant
Location: chr19:42291633 (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 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
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr 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-pro1834leu (accessed [today's date]).

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