Is CIC p.Arg2153Gln (c.6458G>A) pathogenic?

CIC p.Arg2153Gln (c.6458G>A) is classified Likely benign in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-01). AlphaMissense: likely benign (0.0982); Ultra-rare (popmax 0.0173%, mid).

How common is CIC p.Arg2153Gln (c.6458G>A) in the general population?

CIC p.Arg2153Gln (c.6458G>A) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about CIC p.Arg2153Gln (c.6458G>A)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

CIC p.Arg2153Gln

c.6458G>A · rs753703401 · VCV808593

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.084	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 7.5	GERP 0.41, phastCons 1
Overall
CADD	22.4	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 R1244Q vs ClinVar R2153Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% Middle Eastern · 1/5,768 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.00182% 29/1,596,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,768
Admixed American	0.0069%	14,498
South Asian	0.00226%	44,319
European (non-Finnish)	0.00188%	53,305

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.Arg2153Gln
Coding: c.6458G>A
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs753703401
Type: single nucleotide variant
Location: chr19:42293217 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Arg2153Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg2153gln (accessed [today's date]).

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