Is CYFIP2 p.Ile507Phe (c.1519A>T) pathogenic?

CYFIP2 p.Ile507Phe (c.1519A>T) is classified Uncertain significance in CYFIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: ambiguous (0.4917); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.Ile507Phe (c.1519A>T)?

CYFIP2 p.Ile507Phe (c.1519A>T) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.Ile507Phe (c.1519A>T) in the general population?

CYFIP2 p.Ile507Phe (c.1519A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYFIP2 p.Ile507Phe (c.1519A>T)?

AlphaMissense predicts ambiguous (score 0.4917) — an in-silico prediction, not a clinical call.

CYFIP2 p.Ile507Phe

c.1519A>T · VCV4854183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4917 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
AlphaMissense	0.4917	ambiguous
REVEL	0.207	benign-leaning
SaProt	LLR -8.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 11 kb · p 1.8e-21 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYFIP2
Protein: p.Ile507Phe
Coding: c.1519A>T
MANE Select: NM_001037333
Type: single nucleotide variant
Location: chr5:157319924 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.28

Full CYFIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 65 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYFIP2 p.Arg87Cys Pathogenic/Likely pathogenic ★★ same condition
CYFIP2 p.Arg87Pro Pathogenic/Likely pathogenic ★★ same condition
CYFIP2 p.Glu640Lys Pathogenic ★★ same condition
CYFIP2 p.Tyr108His Likely pathogenic ★★ ⚠ same condition
CYFIP2 p.Arg1045Trp Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg353Trp Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Asp821Asn Uncertain significance ★★ ⚠ same condition
CYFIP2 p.His417Asn 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/cyfip2-p-ile507phe (accessed [today's date]).

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