Is CIC p.Gly1697Ser (c.5089G>A) pathogenic?

CIC p.Gly1697Ser (c.5089G>A) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-02). AlphaMissense: likely benign (0.0508); Ultra-rare (popmax 0.0166%, mid).

How common is CIC p.Gly1697Ser (c.5089G>A) in the general population?

CIC p.Gly1697Ser (c.5089G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about CIC p.Gly1697Ser (c.5089G>A)?

AlphaMissense predicts likely benign (score 0.0508) — an in-silico prediction, not a clinical call.

CIC p.Gly1697Ser

c.5089G>A · rs770192319 · VCV2582202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0508 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0508	likely benign
REVEL	0.067	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -2.7, phastCons 0.93
Overall
CADD	11.56	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 and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G788S vs ClinVar G1697S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000275% 4/1,456,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,020
Remaining individualsnot grpmax-eligible	0.00161%	62,192
European (non-Finnish)	0.00017%	588,228

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.Gly1697Ser
Coding: c.5089G>A
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs770192319
Type: single nucleotide variant
Location: chr19:42291130 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Gly1697Val Uncertain significance ★ ⚠ 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-gly1697ser (accessed [today's date]).

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