Is CIC p.Pro1298Ala (c.3892C>G) pathogenic?

CIC p.Pro1298Ala (c.3892C>G) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-09). AlphaMissense: likely benign (0.0612); Ultra-rare (popmax 0.0217%, amr); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Pro1298Ala (c.3892C>G)?

CIC p.Pro1298Ala (c.3892C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Pro1298Ala (c.3892C>G) in the general population?

CIC p.Pro1298Ala (c.3892C>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CIC p.Pro1298Ala (c.3892C>G)?

AlphaMissense predicts likely benign (score 0.0612) — an in-silico prediction, not a clinical call.

CIC p.Pro1298Ala

c.3892C>G · rs199556766 · VCV929081

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0612 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0612	likely benign
REVEL	0.047	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 0.84	GERP -2.3, phastCons 0.18
Overall
CADD	18.28	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 P389A vs ClinVar P1298A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/60,032 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00105% 17/1,613,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,618
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	8.47e-05%	1,180,025

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.Pro1298Ala
Coding: c.3892C>G
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs199556766
Type: single nucleotide variant
Location: chr19:42289211 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg1481Gln 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-pro1298ala (accessed [today's date]).

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