Is CIC p.Phe1310Leu (c.3928T>C) pathogenic?

CIC p.Phe1310Leu (c.3928T>C) is classified Uncertain significance in CIC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.8278); Ultra-rare (popmax 0.0167%, mid); Associated with intellectual developmental disorder, autosomal dominant 45.

What condition is associated with CIC p.Phe1310Leu (c.3928T>C)?

CIC p.Phe1310Leu (c.3928T>C) is associated with intellectual developmental disorder, autosomal dominant 45 (ClinVar).

How common is CIC p.Phe1310Leu (c.3928T>C) in the general population?

CIC p.Phe1310Leu (c.3928T>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CIC p.Phe1310Leu (c.3928T>C)?

AlphaMissense predicts likely pathogenic (score 0.8278) — an in-silico prediction, not a clinical call.

CIC p.Phe1310Leu

c.3928T>C · rs752892028 · VCV2690927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

intellectual developmental disorder, autosomal dominant 45

Computational evidence

Protein change
AlphaMissense	0.8278	likely pathogenic
REVEL	0.304	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Overall
CADD	22.9	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 F401L vs ClinVar F1310L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,972 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000558% 9/1,613,550 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,972
South Asian	0.0022%	45,542
European (non-Finnish)	0.000508%	196,670

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.Phe1310Leu
Coding: c.3928T>C
MANE Select: NM_005984 · reported on NM_001386298
dbSNP: rs752892028
Type: single nucleotide variant
Location: chr19:42289247 (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-phe1310leu (accessed [today's date]).

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