Is CIC p.Pro1529Ser (c.4585C>T) pathogenic?

CIC p.Pro1529Ser (c.4585C>T) is classified Likely benign in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1073); Ultra-rare (popmax 0.0226%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CIC p.Pro1529Ser (c.4585C>T)?

CIC p.Pro1529Ser (c.4585C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CIC p.Pro1529Ser (c.4585C>T) in the general population?

CIC p.Pro1529Ser (c.4585C>T) is ultra-rare (popmax 0.0226%, nfe) (gnomAD).

What do computational predictors say about CIC p.Pro1529Ser (c.4585C>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

CIC p.Pro1529Ser

c.4585C>T · rs138450756 · VCV3144963

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.082	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.5, phastCons 0.99
Overall
CADD	21.1	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 P620S vs ClinVar P1529S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0226% European (non-Finnish) · 267/1,179,980 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.018% 290/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0226%	4,419
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.00801%	12,489
Admixed American	0.005%	20,002

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.Pro1529Ser
Coding: c.4585C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs138450756
Type: single nucleotide variant
Location: chr19:42290626 (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-pro1529ser (accessed [today's date]).

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