Is CIC p.Pro728Ser (c.2182C>T) pathogenic?

CIC p.Pro728Ser (c.2182C>T) is classified Uncertain significance in CIC (ClinVar, Single submitter, 2 submitters; last evaluated 2021-02-19). Ultra-rare (popmax 0.0185%, afr); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Pro728Ser (c.2182C>T)?

CIC p.Pro728Ser (c.2182C>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Pro728Ser (c.2182C>T) in the general population?

CIC p.Pro728Ser (c.2182C>T) is ultra-rare (popmax 0.0185%, afr) (gnomAD).

CIC p.Pro728Ser

c.2182C>T · rs970794792 · VCV1341902

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, afr)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP 1.2, phastCons 0.24
Overall
CADD	9.299	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0185% African / African-American · 9/48,624 alleles

Filtering AF 0.00957% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.00276% 11/398,772 alleles · ultra-rare exomes 1/246,584 · genomes 10/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0185%	5,403
Admixed American	0.0044%	22,724
European (non-Finnish)	0.000442%	226,292

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.Pro728Ser
Coding: c.2182C>T
MANE Select: NM_001386298
dbSNP: rs970794792
Type: single nucleotide variant
Location: chr19:42273965 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ same condition
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr 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-pro728ser (accessed [today's date]).

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