Is CYFIP2 p.Ala146= (c.438C>T) pathogenic?

CYFIP2 p.Ala146= (c.438C>T) is classified Benign/Likely benign in CYFIP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Rare (popmax 0.25%, nfe); Associated with developmental and epileptic encephalopathy, 65.

What condition is associated with CYFIP2 p.Ala146= (c.438C>T)?

CYFIP2 p.Ala146= (c.438C>T) is associated with developmental and epileptic encephalopathy, 65 (ClinVar).

How common is CYFIP2 p.Ala146= (c.438C>T) in the general population?

CYFIP2 p.Ala146= (c.438C>T) is rare (popmax 0.25%, nfe) (gnomAD).

CYFIP2 p.Ala146=

c.438C>T · rs375762537 · VCV774179

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.25%, nfe)

Conditions

developmental and epileptic encephalopathy, 65

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.6
Overall
CADD	0.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.25% European (non-Finnish) · 2,952/1,179,088 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.24%

Overall 0.205% 3,313/1,612,582 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.987%	101
European (non-Finnish)grpmax	0.25%	399
Middle Eastern	0.182%	550
Remaining individualsnot grpmax-eligible	0.154%	650
South Asian	0.146%	684
Ashkenazi Jewishnot grpmax-eligible	0.112%	894
Finnishnot grpmax-eligible	0.0532%	1,881
African / African-American	0.036%	2,777
Admixed American	0.0284%	3,523
East Asian	0.00223%	44,850

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala146=
Coding: c.438C>T
MANE Select: NM_001037333
dbSNP: rs375762537
Type: single nucleotide variant
Location: chr5:157300765 (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

FNDC9 p.Ser146Phe Uncertain significance ★ ⚠ 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-ala146 (accessed [today's date]).

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