Is CYFIP2 p.Asp699His (c.2095G>C) pathogenic?

CYFIP2 p.Asp699His (c.2095G>C) is classified Pathogenic in CYFIP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-04-28). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.Asp699His (c.2095G>C)?

CYFIP2 p.Asp699His (c.2095G>C) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.Asp699His (c.2095G>C) in the general population?

CYFIP2 p.Asp699His (c.2095G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYFIP2 p.Asp699His (c.2095G>C)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

CYFIP2 p.Asp699His

c.2095G>C · rs1581069143 · VCV973752

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic ✓ concordant with ClinVar · top 6% in CYFIP2
REVEL	0.722	pathogenic-leaning
SaProt	LLR -14.82	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 1,767 bp · p 9.7e-06 · regional, not allelic
Overall
CADD	30.0	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 D724H vs ClinVar D699H) — verify the residue.

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.Asp699His
Coding: c.2095G>C
MANE Select: NM_001037333
dbSNP: rs1581069143
Type: single nucleotide variant
Location: chr5:157327988 (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.Asp699Gly Likely pathogenic ★ same residue
CYFIP2 p.Asp699Tyr Likely pathogenic ★ same residue
CYFIP2 p.Asp699= Likely benign ★ same residue
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

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-asp699his (accessed [today's date]).

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