Is CYFIP2 p.Met775Val (c.2323A>G) pathogenic?

CYFIP2 p.Met775Val (c.2323A>G) is classified Conflicting classifications of pathogenicity in CYFIP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.02%, afr).

How common is CYFIP2 p.Met775Val (c.2323A>G) in the general population?

CYFIP2 p.Met775Val (c.2323A>G) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about CYFIP2 p.Met775Val (c.2323A>G)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

CYFIP2 p.Met775Val

c.2323A>G · rs915714723 · VCV1982608

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 32 kb · p 9.5e-12 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M800V vs ClinVar M775V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,948 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00155% 25/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,997
Admixed American	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asian	0.0011%	91,096
European (non-Finnish)	0.000339%	294,976

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.Met775Val
Coding: c.2323A>G
MANE Select: NM_001037333
dbSNP: rs915714723
Type: single nucleotide variant
Location: chr5:157333384 (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-met775val (accessed [today's date]).

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