Is CYFIP1 p.Val480Ile (c.1438G>A) pathogenic?

CYFIP1 p.Val480Ile (c.1438G>A) is classified Uncertain significance in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely benign (0.0653); Ultra-rare (popmax 0.0329%, mid).

How common is CYFIP1 p.Val480Ile (c.1438G>A) in the general population?

CYFIP1 p.Val480Ile (c.1438G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CYFIP1 p.Val480Ile (c.1438G>A)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

CYFIP1 p.Val480Ile

c.1438G>A · rs760215233 · VCV2556683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
SaProt	LLR -4.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP -0.26, phastCons 0.3
Regional constraint	o/e 0.83	unconstrained · MANE · 57 kb · p 5.3e-08 · regional, not allelic
Overall
CADD	19.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00378% 61/1,613,292 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0096%	10,412
Finnishnot grpmax-eligible	0.00626%	15,969
South Asian	0.00549%	18,214
Admixed American	0.00501%	19,979
East Asian	0.00446%	22,439
European (non-Finnish)	0.00322%	31,041
African / African-American	0.00134%	74,892

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: CYFIP1
Protein: p.Val480Ile
Coding: c.1438G>A
MANE Select: NM_014608
dbSNP: rs760215233
Type: single nucleotide variant
Location: chr15:22918780 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 5 PDB
Residue 480: an α-helix

Full CYFIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYFIP1 p.Phe600Leu Uncertain significance ★★ ⚠ same type
CYFIP1 c.3043-4C>G Benign/Likely benign ★★ same type
CYFIP1 p.Ala1003Val Benign ★★ ⚠ same type
CYFIP1 p.Ala385Thr Benign ★★ ⚠ same type
CYFIP1 p.Glu347= Benign ★★ same type
CYFIP1 p.Gly903Ser Benign/Likely benign ★★ same type
CYFIP1 p.Ile795Val Benign ★★ same type
CYFIP1 p.Leu1201= Benign ★★ same type

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/cyfip1-p-val480ile (accessed [today's date]).

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