Is CIC p.Pro2503fs (c.7506dup) pathogenic?

CIC p.Pro2503fs (c.7506dup) is classified Uncertain significance in CIC (ClinVar, Single submitter, 3 submitters; last evaluated 2022-05-04). Rare (popmax 0.112%, mid); Associated with NK-cell enteropathy.

What condition is associated with CIC p.Pro2503fs (c.7506dup)?

CIC p.Pro2503fs (c.7506dup) is associated with NK-cell enteropathy, intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Pro2503fs (c.7506dup) in the general population?

CIC p.Pro2503fs (c.7506dup) is rare (popmax 0.112%, mid) (gnomAD).

How is NK-cell enteropathy inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

CIC p.Pro2503fs

c.7506dup · rs1422380205 · VCV638626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.112%, mid)

Conditions

NK-cell enteropathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP -0.7, phastCons 1
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% Middle Eastern · 2/1,788 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.0413% 231/559,032 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.112%	894
Finnishnot grpmax-eligible	0.079%	1,265
Admixed American	0.068%	1,471
Ashkenazi Jewishnot grpmax-eligible	0.0663%	1,509
African / African-American	0.0639%	1,566
European (non-Finnish)	0.0368%	2,718
Remaining individualsnot grpmax-eligible	0.0345%	2,896
South Asian	0.0274%	3,646
East Asian	0.00642%	15,572

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.Pro2503fs
Coding: c.7506dup
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs1422380205
Type: Duplication
Location: chr19:42295142 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

NK-cell enteropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual developmental disorder, autosomal dominant 45

For NK-cell enteropathy (Orphanet):

Inheritance: Not applicable
Onset: Adult

Similar variants

CIC p.Pro2507fs Uncertain significance ★★ same condition
CIC p.Arg688fs Pathogenic ★ same condition
CIC p.Cys397fs Likely pathogenic ★ same condition
CIC p.Gly1425fs Pathogenic ★ same condition
CIC p.Pro368fs Pathogenic ★ same condition
CIC p.Ser2026fs Pathogenic ★ same condition
CIC p.Trp343fs Likely pathogenic ★ same condition
CIC p.Glu1513fs 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-pro2503fs (accessed [today's date]).

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