Is CIC p.Lys94Arg (c.281A>G) pathogenic?

CIC p.Lys94Arg (c.281A>G) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.3%, sas); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Lys94Arg (c.281A>G)?

CIC p.Lys94Arg (c.281A>G) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Lys94Arg (c.281A>G) in the general population?

CIC p.Lys94Arg (c.281A>G) is low-frequency (popmax 1.3%, sas) (gnomAD).

CIC p.Lys94Arg

c.281A>G · rs539540626 · VCV1301614

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.3%, 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 11	GERP 1.1, phastCons 1
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.3% South Asian · 102/7,868 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.02%

Overall 0.0303% 121/398,950 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.3%	77
Middle Eastern	0.0629%	1,590
Remaining individualsnot grpmax-eligible	0.0216%	4,625
European (non-Finnish)	0.00486%	20,576
African / African-American	0.0041%	24,378
Finnishnot grpmax-eligible	0.00318%	31,464

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.Lys94Arg
Coding: c.281A>G
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs539540626
Type: single nucleotide variant
Location: chr19:42272064 (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-lys94arg (accessed [today's date]).

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