Is CIC p.Ala2500Asp (c.7499C>A) pathogenic?

CIC p.Ala2500Asp (c.7499C>A) is classified Conflicting classifications of pathogenicity in CIC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-01). AlphaMissense: likely benign (0.1273); Ultra-rare (popmax 0.0111%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Ala2500Asp (c.7499C>A)?

CIC p.Ala2500Asp (c.7499C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Ala2500Asp (c.7499C>A) in the general population?

CIC p.Ala2500Asp (c.7499C>A) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about CIC p.Ala2500Asp (c.7499C>A)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

CIC p.Ala2500Asp

c.7499C>A · rs754808317 · VCV2650025

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.19, phastCons 0.001
Overall
CADD	14.33	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1591D vs ClinVar A2500D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 121/1,085,690 alleles

Filtering AF 0.00952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00891%

Overall 0.00894% 129/1,443,320 alleles · ultra-rare exomes 125/1,291,228 · genomes 4/152,092 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0124%	8,047
European (non-Finnish)grpmax	0.0111%	8,973
African / African-American	0.00142%	70,502

Remaining individuals 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.Ala2500Asp
Coding: c.7499C>A
MANE Select: NM_001386298
dbSNP: rs754808317
Type: single nucleotide variant
Location: chr19:42295136 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC c.2795-2056C>T Uncertain significance ★★ same condition
CIC p.Ala1228Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1445Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala1750Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala1975Gly Uncertain significance ★★ ⚠ same condition
CIC p.Ala2463Thr Uncertain significance ★★ ⚠ same condition
CIC p.Arg1205Trp Uncertain significance ★★ ⚠ same condition
CIC p.Arg1481Gln 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-ala2500asp (accessed [today's date]).

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