Is CYFIP1 p.Arg726Trp (c.2176C>T) pathogenic?

CYFIP1 p.Arg726Trp (c.2176C>T) is classified Uncertain significance in CYFIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-24). AlphaMissense: ambiguous (0.3597); Very rare (popmax 0.00445%, eas).

How common is CYFIP1 p.Arg726Trp (c.2176C>T) in the general population?

CYFIP1 p.Arg726Trp (c.2176C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about CYFIP1 p.Arg726Trp (c.2176C>T)?

AlphaMissense predicts ambiguous (score 0.3597) — an in-silico prediction, not a clinical call.

CYFIP1 p.Arg726Trp

c.2176C>T · rs748787369 · VCV2535085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3597 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Computational evidence

Protein change
AlphaMissense	0.3597	ambiguous
SaProt	LLR -10.48	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.85 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 57 kb · p 5.3e-08 · regional, not allelic
Overall
CADD	29.2	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 0.00445% East Asian · 2/44,906 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00297% 48/1,613,976 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,453
European (non-Finnish)	0.00347%	28,779
African / African-American	0.00267%	37,460
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg726Trp
Coding: c.2176C>T
MANE Select: NM_014608
dbSNP: rs748787369
Type: single nucleotide variant
Location: chr15:22910612 (GRCh38)
Gene constraint: LOEUF 0.44 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 5 PDB
Residue 726: 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-arg726trp (accessed [today's date]).

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