Is CYFIP1 p.Leu1226Val (c.3676C>G) pathogenic?

CYFIP1 p.Leu1226Val (c.3676C>G) is classified Uncertain significance in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.122); Ultra-rare (popmax 0.0164%, mid).

How common is CYFIP1 p.Leu1226Val (c.3676C>G) in the general population?

CYFIP1 p.Leu1226Val (c.3676C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CYFIP1 p.Leu1226Val (c.3676C>G)?

AlphaMissense predicts likely benign (score 0.122) — an in-silico prediction, not a clinical call.

CYFIP1 p.Leu1226Val

c.3676C>G · VCV4657963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.122 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.122	likely benign
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.49	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.1	GERP -3.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,902 bp · p 0.37 · regional, not allelic
Overall
CADD	17.89	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,612,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00401%	24,947
European (non-Finnish)	0.000254%	393,210

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.Leu1226Val
Coding: c.3676C>G
MANE Select: NM_014608
Type: single nucleotide variant
Location: chr15:22870114 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 5 PDB

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-leu1226val (accessed [today's date]).

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