Is CYFIP2 p.Ile761Val (c.2281A>G) pathogenic?

CYFIP2 p.Ile761Val (c.2281A>G) is classified Conflicting classifications of pathogenicity in CYFIP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.1027); Ultra-rare (popmax 0.012%, afr); Associated with Inborn genetic diseases.

What condition is associated with CYFIP2 p.Ile761Val (c.2281A>G)?

CYFIP2 p.Ile761Val (c.2281A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CYFIP2 p.Ile761Val (c.2281A>G) in the general population?

CYFIP2 p.Ile761Val (c.2281A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CYFIP2 p.Ile761Val (c.2281A>G)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

CYFIP2 p.Ile761Val

c.2281A>G · rs549089526 · VCV1562634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 32 kb · p 9.5e-12 · regional, not allelic
Overall
CADD	24.2	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 I786V vs ClinVar I761V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,888 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00341% 55/1,613,778 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,321
European (non-Finnish)	0.00348%	28,777
South Asian	0.00329%	30,359
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Ile761Val
Coding: c.2281A>G
MANE Select: NM_001037333
dbSNP: rs549089526
Type: single nucleotide variant
Location: chr5:157333342 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYFIP2 p.Ile761= Likely benign ★ same residue
CYFIP2 p.Glu640Lys Pathogenic ★★ same condition
CYFIP2 p.Ala1074Thr Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1041His Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1098His Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1098Leu Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1100Trp Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1206Trp 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-ile761val (accessed [today's date]).

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