Is CYFIP1 p.Ser90Phe (c.269C>T) pathogenic?

CYFIP1 p.Ser90Phe (c.269C>T) is classified Uncertain significance in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.9947); Very rare (popmax 0.00585%, nfe).

How common is CYFIP1 p.Ser90Phe (c.269C>T) in the general population?

CYFIP1 p.Ser90Phe (c.269C>T) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about CYFIP1 p.Ser90Phe (c.269C>T)?

AlphaMissense predicts likely pathogenic (score 0.9947) — an in-silico prediction, not a clinical call.

CYFIP1 p.Ser90Phe

c.269C>T · VCV3837711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.9947	likely pathogenic · top 10% in CYFIP1
SaProt	LLR -12.62	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 9.6	GERP 2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 7,965 bp · p 1.7e-09 · regional, not allelic
Overall
CADD	29.5	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

Grpmax group 0.00585% European (non-Finnish) · 69/1,180,000 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00479% 70/1,461,812 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,101
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Ser90Phe
Coding: c.269C>T
MANE Select: NM_014608
Type: single nucleotide variant
Location: chr15:22944878 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 5 PDB
Residue 90: 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-ser90phe (accessed [today's date]).

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