Is CIC p.Pro960Ser (c.2878C>T) pathogenic?

CIC p.Pro960Ser (c.2878C>T) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00449%, nfe); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Pro960Ser (c.2878C>T)?

CIC p.Pro960Ser (c.2878C>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Pro960Ser (c.2878C>T) in the general population?

CIC p.Pro960Ser (c.2878C>T) is very rare (popmax 0.00449%, nfe) (gnomAD).

What do computational predictors say about CIC p.Pro960Ser (c.2878C>T)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

CIC p.Pro960Ser

c.2878C>T · rs756596852 · VCV2440084

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.069	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 7.6	GERP 0.97, phastCons 1
Overall
CADD	23.3	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 P51S vs ClinVar P960S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00449% European (non-Finnish) · 53/1,179,992 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00383% 56/1,461,568 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00449%	22,264
Remaining individualsnot grpmax-eligible	0.0032%	31,251
African / African-American	0.00133%	75,028

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.Pro960Ser
Coding: c.2878C>T
MANE Select: NM_001386298
dbSNP: rs756596852
Type: single nucleotide variant
Location: chr19:42286854 (GRCh38)
Structure: AlphaFold pLDDT 75.09

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

Disease context

intellectual developmental disorder, autosomal dominant 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIC p.Pro960= Likely benign ★ same residue
CIC c.3179+1G>T Pathogenic ★★ same condition
CIC c.5903-2A>G Likely pathogenic ★★ same condition
CIC p.Asn1136Ser Likely pathogenic ★★ same condition
CIC p.Gln1134Ter Pathogenic ★★ same condition
CIC p.Gln1799Ter Likely pathogenic ★★ same condition
CIC p.Ala1761Val Uncertain significance ★★ ⚠ same condition
CIC p.Ala2064Thr 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-pro960ser (accessed [today's date]).

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