Is CYFIP2 p.Pro117Ser (c.349C>T) pathogenic?

CYFIP2 p.Pro117Ser (c.349C>T) is classified Conflicting classifications of pathogenicity in CYFIP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.888); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CYFIP2 p.Pro117Ser (c.349C>T)?

CYFIP2 p.Pro117Ser (c.349C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CYFIP2 p.Pro117Ser (c.349C>T) in the general population?

CYFIP2 p.Pro117Ser (c.349C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CYFIP2 p.Pro117Ser (c.349C>T)?

AlphaMissense predicts likely pathogenic (score 0.888) — an in-silico prediction, not a clinical call.

CYFIP2 p.Pro117Ser

c.349C>T · rs750559695 · VCV1982330

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.888	likely pathogenic
REVEL	0.311	indeterminate
SaProt	LLR -11.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 19 kb · p 1.4e-27 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,738 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,470 alleles · very rare

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.Pro117Ser
Coding: c.349C>T
MANE Select: NM_001037333
dbSNP: rs750559695
Type: single nucleotide variant
Location: chr5:157296736 (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.Pro117Gln Uncertain significance ★ ⚠ same residue
CYFIP2 p.Pro117= Likely benign ★ same residue
CYFIP2 p.Pro117Leu 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

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-pro117ser (accessed [today's date]).

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