Is CIC p.Ser2183Leu (c.6548C>T) pathogenic?

CIC p.Ser2183Leu (c.6548C>T) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0828); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Ser2183Leu (c.6548C>T)?

CIC p.Ser2183Leu (c.6548C>T) is associated with Inborn genetic diseases, intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Ser2183Leu (c.6548C>T) in the general population?

CIC p.Ser2183Leu (c.6548C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CIC p.Ser2183Leu (c.6548C>T)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

CIC p.Ser2183Leu

c.6548C>T · VCV3583924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.067	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.2	GERP 1.7, phastCons 1
Overall
CADD	26.9	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 S1274L vs ClinVar S2183L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,996 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
African / African-American	0.00267%	37,477

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.Ser2183Leu
Coding: c.6548C>T
MANE Select: NM_005984 · reported on NM_001386298
Type: single nucleotide variant
Location: chr19:42293617 (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

Also linked: intellectual developmental disorder, autosomal dominant 45

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 c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly 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-ser2183leu (accessed [today's date]).

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