Is CYFIP2 p.Arg148Cys (c.442C>T) pathogenic?

CYFIP2 p.Arg148Cys (c.442C>T) is classified Uncertain significance in CYFIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-19). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 0.00167%, amr).

How common is CYFIP2 p.Arg148Cys (c.442C>T) in the general population?

CYFIP2 p.Arg148Cys (c.442C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CYFIP2 p.Arg148Cys (c.442C>T)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

CYFIP2 p.Arg148Cys

c.442C>T · rs1758680375 · VCV1711892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic
REVEL	0.271	benign-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP 0.84, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 19 kb · p 1.4e-27 · regional, not allelic
Overall
CADD	25.3	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 0.00167% Admixed American · 1/59,884 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000372% 6/1,612,812 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,884
Remaining individualsnot grpmax-eligible	0.0016%	62,412
African / African-American	0.00134%	74,876
European (non-Finnish)	0.000254%	393,103

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.Arg148Cys
Coding: c.442C>T
MANE Select: NM_001037333
dbSNP: rs1758680375
Type: single nucleotide variant
Location: chr5:157300769 (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-arg148cys (accessed [today's date]).

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