Is CYFIP2 p.Arg963Ter (c.2887C>T) pathogenic?

CYFIP2 p.Arg963Ter (c.2887C>T) is classified Uncertain significance in CYFIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). Very rare (popmax 0.00133%, afr).

How common is CYFIP2 p.Arg963Ter (c.2887C>T) in the general population?

CYFIP2 p.Arg963Ter (c.2887C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

CYFIP2 p.Arg963Ter

c.2887C>T · rs1337845533 · VCV2711338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 25 of 31
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.39	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,916 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,650 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,916
European (non-Finnish)	0.00017%	589,877

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.Arg963Ter
Coding: c.2887C>T
MANE Select: NM_001037333
dbSNP: rs1337845533
Type: single nucleotide variant
Location: chr5:157360351 (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

Similar variants

CYFIP2 p.Arg87Cys Pathogenic/Likely pathogenic ★★ same type
CYFIP2 p.Arg87Pro Pathogenic/Likely pathogenic ★★ same type
CYFIP2 p.Glu640Lys Pathogenic ★★ same type
CYFIP2 p.Tyr108His Likely pathogenic ★★ ⚠ same type
CYFIP2 p.Ala1074Thr Uncertain significance ★★ ⚠ same type
CYFIP2 p.Ala773Thr Uncertain significance ★★ ⚠ same type
CYFIP2 p.Ala80Val Uncertain significance ★★ ⚠ same type
CYFIP2 p.Arg1041His Uncertain significance ★★ ⚠ 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/cyfip2-p-arg963ter (accessed [today's date]).

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