Is CIC p.Leu2280Pro (c.6839T>C) pathogenic?

CIC p.Leu2280Pro (c.6839T>C) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-27). AlphaMissense: likely pathogenic (0.9968); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Leu2280Pro (c.6839T>C)?

CIC p.Leu2280Pro (c.6839T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Leu2280Pro (c.6839T>C) in the general population?

CIC p.Leu2280Pro (c.6839T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CIC p.Leu2280Pro (c.6839T>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

CIC p.Leu2280Pro

c.6839T>C · rs1383222581 · VCV2339360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 9% in CIC
REVEL	0.233	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.2, phastCons 1
Overall
CADD	25.3	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 L1371P vs ClinVar L2280P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 0.000124% 2/1,613,498 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,554
European (non-Finnish)grpmax	8.47e-05%	1,180,002

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu2280Pro
Coding: c.6839T>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs1383222581
Type: single nucleotide variant
Location: chr19:42294006 (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 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
CIC p.Arg1481Gln 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-leu2280pro (accessed [today's date]).

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