Is CIC p.Ser2167Gly (c.6499A>G) pathogenic?

CIC p.Ser2167Gly (c.6499A>G) is classified Likely benign in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-20). AlphaMissense: likely benign (0.0553); Very rare (popmax 0.0054%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Ser2167Gly (c.6499A>G)?

CIC p.Ser2167Gly (c.6499A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Ser2167Gly (c.6499A>G) in the general population?

CIC p.Ser2167Gly (c.6499A>G) is very rare (popmax 0.0054%, nfe) (gnomAD).

What do computational predictors say about CIC p.Ser2167Gly (c.6499A>G)?

AlphaMissense predicts likely benign (score 0.0553) — an in-silico prediction, not a clinical call.

CIC p.Ser2167Gly

c.6499A>G · rs774014216 · VCV2593241

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0553 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0054%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0553	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -3.4, phastCons 0.006
Overall
CADD	1.019	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 S1258G vs ClinVar S2167G) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0054% European (non-Finnish) · 63/1,167,494 alleles

Filtering AF 0.00431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00392%

Overall 0.00423% 67/1,584,354 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0054%	18,532
Remaining individualsnot grpmax-eligible	0.00489%	20,459
African / African-American	0.00135%	74,186

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.Ser2167Gly
Coding: c.6499A>G
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs774014216
Type: single nucleotide variant
Location: chr19:42293258 (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

Similar variants

CIC c.2795-2056C>T Uncertain significance ★★ ⚠ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg1481Gln 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-ser2167gly (accessed [today's date]).

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