Is CIC p.Lys1546del (c.4636_4638del) pathogenic?

CIC p.Lys1546del (c.46364638del) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-02-01). Ultra-rare (popmax 0.0144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Lys1546del (c.4636_4638del)?

CIC p.Lys1546del (c.4636_4638del) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Lys1546del (c.4636_4638del) in the general population?

CIC p.Lys1546del (c.4636_4638del) is ultra-rare (popmax 0.0144%, nfe) (gnomAD).

CIC p.Lys1546del

c.4636_4638del · rs587778196 · VCV133894

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP 1.5, phastCons 1
Overall
CADD	16.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0144% European (non-Finnish) · 170/1,179,936 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0126% 203/1,613,214 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0144%	6,941
Admixed American	0.0133%	7,503
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00933%	10,722
South Asian	0.00878%	11,385
East Asian	0.00669%	14,958

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.Lys1546del
Coding: c.4636_4638del
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs587778196
Type: Deletion
Location: chr19:42290677 (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.Lys1546Glu Likely benign ★ same residue
CIC p.Pro1240fs Pathogenic ★ same condition
SLC25A1 p.Cys127fs Pathogenic ★ same condition
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

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-lys1546del (accessed [today's date]).

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