Is CIC p.Val989Ala (c.2966T>C) pathogenic?

CIC p.Val989Ala (c.2966T>C) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-17). AlphaMissense: ambiguous (0.3534); Very rare (popmax 0.00763%, nfe); Associated with CIC-related disorder.

What condition is associated with CIC p.Val989Ala (c.2966T>C)?

CIC p.Val989Ala (c.2966T>C) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Val989Ala (c.2966T>C) in the general population?

CIC p.Val989Ala (c.2966T>C) is very rare (popmax 0.00763%, nfe) (gnomAD).

What do computational predictors say about CIC p.Val989Ala (c.2966T>C)?

AlphaMissense predicts ambiguous (score 0.3534) — an in-silico prediction, not a clinical call.

CIC p.Val989Ala

c.2966T>C · rs994708612 · VCV2629813

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00763%, nfe)

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.3534	ambiguous
REVEL	0.062	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.2, phastCons 1
Overall
CADD	22.4	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 V80A vs ClinVar V989A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00763% European (non-Finnish) · 90/1,179,960 alleles

Filtering AF 0.00631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00584%

Overall 0.00565% 91/1,610,828 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00763%	13,111
Remaining individualsnot grpmax-eligible	0.0016%	62,400

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.Val989Ala
Coding: c.2966T>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs994708612
Type: single nucleotide variant
Location: chr19:42287027 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

CIC-related disorder

Similar variants

CIC p.Asn1136Ser Likely pathogenic ★★ same condition
SLC25A1 p.Ala274Val Pathogenic/Likely pathogenic ★★ same condition
SLC25A1 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
CIC p.Arg2114Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg800His Uncertain significance ★★ same condition
CIC p.Gly17Val Uncertain significance ★★ same condition
CIC p.Arg800Cys Likely pathogenic ★ same condition
CIC c.7186+3G>T 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-val989ala (accessed [today's date]).

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