Is CIC p.Ser442Ala (c.1324T>G) pathogenic?

CIC p.Ser442Ala (c.1324T>G) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-06). Ultra-rare (popmax 0.0253%, sas); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Ser442Ala (c.1324T>G)?

CIC p.Ser442Ala (c.1324T>G) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Ser442Ala (c.1324T>G) in the general population?

CIC p.Ser442Ala (c.1324T>G) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

CIC p.Ser442Ala

c.1324T>G · rs2036846589 · VCV1696696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

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 7.8	GERP 1.2, phastCons 1
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 2/7,908 alleles

Filtering AF 0.00446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.001% 4/398,322 alleles · ultra-rare exomes 1/246,512 · genomes 3/151,810 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,954
Remaining individualsnot grpmax-eligible	0.00542%	18,458
European (non-Finnish)	0.000442%	226,124

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.Ser442Ala
Coding: c.1324T>G
MANE Select: NM_001386298
dbSNP: rs2036846589
Type: single nucleotide variant
Location: chr19:42273107 (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 p.Ser442= Likely benign ★ same residue
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

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-ser442ala (accessed [today's date]).

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