Is CIC p.Arg1498Gln (c.4493G>A) pathogenic?

CIC p.Arg1498Gln (c.4493G>A) is classified Likely benign in CIC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely benign (0.1259); Ultra-rare (popmax 0.0254%, afr); Associated with CIC-related disorder.

What condition is associated with CIC p.Arg1498Gln (c.4493G>A)?

CIC p.Arg1498Gln (c.4493G>A) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Arg1498Gln (c.4493G>A) in the general population?

CIC p.Arg1498Gln (c.4493G>A) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about CIC p.Arg1498Gln (c.4493G>A)?

AlphaMissense predicts likely benign (score 0.1259) — an in-silico prediction, not a clinical call.

CIC p.Arg1498Gln

c.4493G>A · rs202152564 · VCV3038513

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1259 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.1259	likely benign
REVEL	0.091	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	23.5	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 R589Q vs ClinVar R1498Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,858 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00223% 36/1,613,248 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,940
East Asian	0.00892%	11,216
Admixed American	0.00333%	29,991
Remaining individualsnot grpmax-eligible	0.0032%	31,219
European (non-Finnish)	0.000763%	131,095

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.Arg1498Gln
Coding: c.4493G>A
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs202152564
Type: single nucleotide variant
Location: chr19:42290534 (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.Arg1498Trp Uncertain significance ★ ⚠ same residue
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

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-arg1498gln (accessed [today's date]).

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