Is CYFIP1 p.Gln226Pro (c.677A>C) pathogenic?

CYFIP1 p.Gln226Pro (c.677A>C) is classified Uncertain significance in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.9281); Absent from gnomAD v4.1.

How common is CYFIP1 p.Gln226Pro (c.677A>C) in the general population?

CYFIP1 p.Gln226Pro (c.677A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYFIP1 p.Gln226Pro (c.677A>C)?

AlphaMissense predicts likely pathogenic (score 0.9281) — an in-silico prediction, not a clinical call.

CYFIP1 p.Gln226Pro

c.677A>C · VCV4657968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9281 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.9281	likely pathogenic
SaProt	LLR -13.82	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 57 kb · p 5.3e-08 · regional, not allelic
Overall
CADD	24.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYFIP1
Protein: p.Gln226Pro
Coding: c.677A>C
MANE Select: NM_014608
Type: single nucleotide variant
Location: chr15:22939310 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 5 PDB
Residue 226: 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-gln226pro (accessed [today's date]).

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