Is CIC p.Ala1321Val (c.3962C>T) pathogenic?

CIC p.Ala1321Val (c.3962C>T) is classified Likely benign in CIC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-09-15). AlphaMissense: likely benign (0.0976); Rare (popmax 0.123%, afr); Associated with CIC-related disorder.

What condition is associated with CIC p.Ala1321Val (c.3962C>T)?

CIC p.Ala1321Val (c.3962C>T) is associated with CIC-related disorder (ClinVar).

How common is CIC p.Ala1321Val (c.3962C>T) in the general population?

CIC p.Ala1321Val (c.3962C>T) is rare (popmax 0.123%, afr) (gnomAD).

What do computational predictors say about CIC p.Ala1321Val (c.3962C>T)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

CIC p.Ala1321Val

c.3962C>T · rs147328280 · VCV3058142

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CIC-related disorder

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.03	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 2.9	GERP 0.21, phastCons 1
Overall
CADD	17.06	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 A412V vs ClinVar A1321V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.123% African / African-American · 92/75,058 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0948%

Overall 0.00607% 98/1,613,852 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.123%	816
Admixed American	0.005%	20,009
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000169%	590,016

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.Ala1321Val
Coding: c.3962C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs147328280
Type: single nucleotide variant
Location: chr19:42289281 (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.Val989Ala Uncertain significance ★★ ⚠ same condition
CIC p.Arg800Cys Likely pathogenic ★ 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-ala1321val (accessed [today's date]).

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