Is CYFIP2 p.His808Arg (c.2423A>G) pathogenic?

CYFIP2 p.His808Arg (c.2423A>G) is classified Conflicting classifications of pathogenicity in CYFIP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-26). AlphaMissense: likely pathogenic (0.9122); Very rare (popmax 8.48e-05%, nfe); Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.His808Arg (c.2423A>G)?

CYFIP2 p.His808Arg (c.2423A>G) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.His808Arg (c.2423A>G) in the general population?

CYFIP2 p.His808Arg (c.2423A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CYFIP2 p.His808Arg (c.2423A>G)?

AlphaMissense predicts likely pathogenic (score 0.9122) — an in-silico prediction, not a clinical call.

CYFIP2 p.His808Arg

c.2423A>G · VCV3381220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9122 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
AlphaMissense	0.9122	likely pathogenic
REVEL	0.768	pathogenic-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 32 kb · p 9.5e-12 · regional, not allelic
Overall
CADD	25.8	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 H833R vs ClinVar H808R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 0.000657% 1/152,230 alleles · very rare

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: CYFIP2
Protein: p.His808Arg
Coding: c.2423A>G
MANE Select: NM_001037333
Type: single nucleotide variant
Location: chr5:157339094 (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-his808arg (accessed [today's date]).

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