Is CIC p.Ala1694Ser (c.5080G>T) pathogenic?

CIC p.Ala1694Ser (c.5080G>T) is classified Likely benign in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0641); Very rare (popmax 0.00085%, nfe).

How common is CIC p.Ala1694Ser (c.5080G>T) in the general population?

CIC p.Ala1694Ser (c.5080G>T) is very rare (popmax 0.00085%, nfe) (gnomAD).

What do computational predictors say about CIC p.Ala1694Ser (c.5080G>T)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

CIC p.Ala1694Ser

c.5080G>T · VCV3911403

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00085%, nfe)

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.329	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -2.7, phastCons 0.002
Overall
CADD	4.125	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 A785S vs ClinVar A1694S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00085% European (non-Finnish) · 10/1,176,878 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000683% 11/1,609,374 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00158%	63,490
European (non-Finnish)grpmax	0.00085%	117,688

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1694Ser
Coding: c.5080G>T
MANE Select: NM_005984 · reported on NM_001386298
Type: single nucleotide variant
Location: chr19:42291121 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

CIC p.Ala1694Val Uncertain significance ★ same residue
CIC p.Ala1694fs Likely pathogenic ★ 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

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-ala1694ser (accessed [today's date]).

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