Is CIC p.Ser2006Cys (c.6017C>G) pathogenic?

CIC p.Ser2006Cys (c.6017C>G) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely benign (0.1369); Very rare (popmax 8.47e-05%, nfe).

How common is CIC p.Ser2006Cys (c.6017C>G) in the general population?

CIC p.Ser2006Cys (c.6017C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CIC p.Ser2006Cys (c.6017C>G)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

CIC p.Ser2006Cys

c.6017C>G · rs2147308954 · VCV3251820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.37	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Overall
CADD	22.6	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S1097C vs ClinVar S2006C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,970 alleles

Overall 6.84e-05% 1/1,461,564 alleles · very rare

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.Ser2006Cys
Coding: c.6017C>G
MANE Select: NM_001386298
dbSNP: rs2147308954
Type: single nucleotide variant
Location: chr19:42292680 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Ser2006= Benign/Likely benign ★★ same residue
CIC c.3179+1G>A Likely pathogenic ★★ same type
CIC c.3179+1G>T Pathogenic ★★ same type
CIC c.5903-2A>G Likely pathogenic ★★ same type
CIC p.Asn1136Ser Likely pathogenic ★★ same type
CIC p.Gln1134Ter Pathogenic ★★ same type
CIC p.Gln1799Ter Likely pathogenic ★★ same type
SLC25A1 c.821+1G>A Pathogenic ★★ same type

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-ser2006cys (accessed [today's date]).

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