Is CIC p.Pro1067Arg (c.3200C>G) pathogenic?

CIC p.Pro1067Arg (c.3200C>G) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-29). AlphaMissense: likely pathogenic (0.6829); Very rare (popmax 0.000339%, nfe).

How common is CIC p.Pro1067Arg (c.3200C>G) in the general population?

CIC p.Pro1067Arg (c.3200C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CIC p.Pro1067Arg (c.3200C>G)?

AlphaMissense predicts likely pathogenic (score 0.6829) — an in-silico prediction, not a clinical call.

CIC p.Pro1067Arg

c.3200C>G · rs759429513 · VCV2574242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6829	likely pathogenic
REVEL	0.2	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Overall
CADD	27.0	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 P158R vs ClinVar P1067R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,038 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,060 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.Pro1067Arg
Coding: c.3200C>G
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs759429513
Type: single nucleotide variant
Location: chr19:42287340 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Pro1067= Likely benign ★ same residue
CIC c.3179+1G>A Likely pathogenic ★★ same type
CIC c.3179+1G>T Pathogenic ★★ same type
CIC c.5903-2A>G Likely pathogenic ★★ same type
CIC p.Asn1136Ser Likely pathogenic ★★ same type
CIC p.Gln1134Ter Pathogenic ★★ same type
CIC p.Gln1799Ter Likely pathogenic ★★ same type
SLC25A1 c.821+1G>A Pathogenic ★★ same type

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-pro1067arg (accessed [today's date]).

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