Is CIC p.Pro1406Leu (c.4217C>T) pathogenic?

CIC p.Pro1406Leu (c.4217C>T) is classified Likely pathogenic in CIC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-13). AlphaMissense: likely pathogenic (0.9431); Very rare (popmax 0.000169%, nfe); Associated with CIC-related disorder.

What condition is associated with CIC p.Pro1406Leu (c.4217C>T)?

CIC p.Pro1406Leu (c.4217C>T) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Pro1406Leu (c.4217C>T) in the general population?

CIC p.Pro1406Leu (c.4217C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CIC p.Pro1406Leu (c.4217C>T)?

AlphaMissense predicts likely pathogenic (score 0.9431) — an in-silico prediction, not a clinical call.

CIC p.Pro1406Leu

c.4217C>T · rs951320175 · VCV2633210

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.9431	likely pathogenic ✓ concordant with ClinVar
REVEL	0.204	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 7.7	GERP 1.7, phastCons 1
Overall
CADD	25.9	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 P497L vs ClinVar P1406L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,972 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.Pro1406Leu
Coding: c.4217C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs951320175
Type: single nucleotide variant
Location: chr19:42290258 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

CIC-related disorder

Similar variants

CIC p.Asn1136Ser Likely pathogenic ★★ same condition
SLC25A1 p.Ala274Val Pathogenic/Likely pathogenic ★★ same condition
SLC25A1 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
CIC p.Arg2114Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg800His Uncertain significance ★★ same condition
CIC p.Gly17Val Uncertain significance ★★ same condition
CIC p.Val989Ala Uncertain significance ★★ ⚠ same condition
CIC p.Arg800Cys Likely 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-pro1406leu (accessed [today's date]).

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