Is CIC p.Pro2506Arg (c.7517C>G) pathogenic?

CIC p.Pro2506Arg (c.7517C>G) is classified Uncertain significance in CIC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1311); Very rare (popmax 0.00991%, afr); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Pro2506Arg (c.7517C>G)?

CIC p.Pro2506Arg (c.7517C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Pro2506Arg (c.7517C>G) in the general population?

CIC p.Pro2506Arg (c.7517C>G) is very rare (popmax 0.00991%, afr) (gnomAD).

What do computational predictors say about CIC p.Pro2506Arg (c.7517C>G)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

CIC p.Pro2506Arg

c.7517C>G · VCV4228898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00991%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.096	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 2.5	GERP 0.21, phastCons 0.99
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1597R vs ClinVar P2506R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00991% African / African-American · 7/70,610 alleles

Filtering AF 0.00461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00324%

Overall 0.00137% 20/1,462,596 alleles · very rare exomes 10/1,310,570 · genomes 10/152,026 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00991%	10,087
Admixed American	0.00506%	19,765
East Asian	0.00246%	40,696
Remaining individualsnot grpmax-eligible	0.00176%	56,826
European (non-Finnish)	0.000811%	123,333

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.Pro2506Arg
Coding: c.7517C>G
MANE Select: NM_001386298
Type: single nucleotide variant
Location: chr19:42295154 (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 p.Pro2506Gln Likely benign ★★ same residue
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

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-pro2506arg (accessed [today's date]).

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