Is CIC p.Ser1094Tyr (c.3281C>A) pathogenic?

CIC p.Ser1094Tyr (c.3281C>A) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.7392); Very rare (popmax 0.00167%, amr).

How common is CIC p.Ser1094Tyr (c.3281C>A) in the general population?

CIC p.Ser1094Tyr (c.3281C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CIC p.Ser1094Tyr (c.3281C>A)?

AlphaMissense predicts likely pathogenic (score 0.7392) — an in-silico prediction, not a clinical call.

CIC p.Ser1094Tyr

c.3281C>A · VCV3378074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7392 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7392	likely pathogenic
REVEL	0.12	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, 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 S185Y vs ClinVar S1094Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,028 alleles

Overall 6.84e-05% 1/1,461,628 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.Ser1094Tyr
Coding: c.3281C>A
MANE Select: NM_005984 · reported on NM_001386298
Type: single nucleotide variant
Location: chr19:42287421 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Similar variants

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
SLC25A1 p.Ala274Val Pathogenic/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-ser1094tyr (accessed [today's date]).

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