Is CYFIP2 p.Ala498Val (c.1493C>T) pathogenic?

CYFIP2 p.Ala498Val (c.1493C>T) is classified Uncertain significance in CYFIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-01). AlphaMissense: likely pathogenic (0.9213); Very rare (popmax 0.00223%, eas); Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.Ala498Val (c.1493C>T)?

CYFIP2 p.Ala498Val (c.1493C>T) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.Ala498Val (c.1493C>T) in the general population?

CYFIP2 p.Ala498Val (c.1493C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CYFIP2 p.Ala498Val (c.1493C>T)?

AlphaMissense predicts likely pathogenic (score 0.9213) — an in-silico prediction, not a clinical call.

CYFIP2 p.Ala498Val

c.1493C>T · rs753188984 · VCV2440666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
AlphaMissense	0.9213	likely pathogenic
REVEL	0.434	indeterminate
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 11 kb · p 1.8e-21 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 0.000137% 2/1,461,666 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
African / African-American	0.00133%	75,050

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.Ala498Val
Coding: c.1493C>T
MANE Select: NM_001037333
dbSNP: rs753188984
Type: single nucleotide variant
Location: chr5:157319898 (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.Ala498= 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
CYFIP2 p.Arg353Trp Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Asp821Asn 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-ala498val (accessed [today's date]).

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