Is CIC p.Pro2506Gln (c.7517C>A) pathogenic?

CIC p.Pro2506Gln (c.7517C>A) is classified Likely benign in CIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0903); Ultra-rare (popmax 0.0228%, mid).

How common is CIC p.Pro2506Gln (c.7517C>A) in the general population?

CIC p.Pro2506Gln (c.7517C>A) is ultra-rare (popmax 0.0228%, mid) (gnomAD).

What do computational predictors say about CIC p.Pro2506Gln (c.7517C>A)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

CIC p.Pro2506Gln

c.7517C>A · rs747297469 · VCV1176081

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0228%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.136	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	17.58	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 P1597Q vs ClinVar P2506Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0228% Middle Eastern · 1/4,388 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.0138% 202/1,462,454 alleles · ultra-rare exomes 190/1,310,548 · genomes 12/151,906 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0228%	4,388
European (non-Finnish)	0.0168%	5,968
Remaining individualsnot grpmax-eligible	0.0141%	7,101
South Asian	0.0068%	14,708
African / African-American	0.00284%	35,244

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.Pro2506Gln
Coding: c.7517C>A
MANE Select: NM_001386298
dbSNP: rs747297469
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

Similar variants

CIC p.Pro2506Arg Uncertain significance ★ ⚠ same residue
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

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-pro2506gln (accessed [today's date]).

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