Is CIC p.Thr2477Met (c.7430C>T) pathogenic?

CIC p.Thr2477Met (c.7430C>T) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.087); Ultra-rare (popmax 0.0191%, mid); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Thr2477Met (c.7430C>T)?

CIC p.Thr2477Met (c.7430C>T) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Thr2477Met (c.7430C>T) in the general population?

CIC p.Thr2477Met (c.7430C>T) is ultra-rare (popmax 0.0191%, mid) (gnomAD).

What do computational predictors say about CIC p.Thr2477Met (c.7430C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

CIC p.Thr2477Met

c.7430C>T · rs920388530 · VCV930872

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.138	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 0.18	GERP -0.83, phastCons 0.014
Overall
CADD	18.97	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 and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T1568M vs ClinVar T2477M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0191% Middle Eastern · 1/5,248 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00285%

Overall 0.00386% 53/1,371,330 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0191%	5,248
Remaining individualsnot grpmax-eligible	0.00673%	14,853
European (non-Finnish)	0.00412%	24,255
South Asian	0.00121%	82,440

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.Thr2477Met
Coding: c.7430C>T
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs920388530
Type: single nucleotide variant
Location: chr19:42295067 (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 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
CIC p.Ala2463Thr 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-thr2477met (accessed [today's date]).

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