Is CYFIP2 p.Arg87Ser (c.259C>A) pathogenic?

CYFIP2 p.Arg87Ser (c.259C>A) is classified Likely pathogenic in CYFIP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-05-28). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.Arg87Ser (c.259C>A)?

CYFIP2 p.Arg87Ser (c.259C>A) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.Arg87Ser (c.259C>A) in the general population?

CYFIP2 p.Arg87Ser (c.259C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYFIP2 p.Arg87Ser (c.259C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CYFIP2 p.Arg87Ser

c.259C>A · rs1131692231 · VCV802171

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 2% in CYFIP2
REVEL	0.602	indeterminate
SaProt	LLR -15.60	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -1.8, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 19 kb · p 1.4e-27 · regional, not allelic
Overall
CADD	27.4	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.Arg87Ser
Coding: c.259C>A
MANE Select: NM_001037333
dbSNP: rs1131692231
Type: single nucleotide variant
Location: chr5:157294834 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.28
Residue 87: a UniProt-annotated variant site (in dee65)

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 residue
CYFIP2 p.Arg87Pro Pathogenic/Likely pathogenic ★★ same residue
CYFIP2 p.Arg87Leu Likely pathogenic ★ same residue
CYFIP2 p.Arg87= Likely benign ★ same residue
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

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-arg87ser (accessed [today's date]).

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