Is CIC p.Gly1623Arg (c.4867G>C) pathogenic?

CIC p.Gly1623Arg (c.4867G>C) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-12). AlphaMissense: likely benign (0.2358); Very rare (popmax 0.00333%, amr); Associated with CIC-related disorder.

What condition is associated with CIC p.Gly1623Arg (c.4867G>C)?

CIC p.Gly1623Arg (c.4867G>C) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Gly1623Arg (c.4867G>C) in the general population?

CIC p.Gly1623Arg (c.4867G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CIC p.Gly1623Arg (c.4867G>C)?

AlphaMissense predicts likely benign (score 0.2358) — an in-silico prediction, not a clinical call.

CIC p.Gly1623Arg

c.4867G>C · rs1291674857 · VCV2629778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.2358	likely benign
REVEL	0.181	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G714R vs ClinVar G1623R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,022 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,204 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.Gly1623Arg
Coding: c.4867G>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs1291674857
Type: single nucleotide variant
Location: chr19:42290908 (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-gly1623arg (accessed [today's date]).

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