Is SCYL2 p.Arg287Cys (c.859C>T) pathogenic?

SCYL2 p.Arg287Cys (c.859C>T) is classified Uncertain significance in SCYL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.1806); Very rare (popmax 0.00157%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SCYL2 p.Arg287Cys (c.859C>T)?

SCYL2 p.Arg287Cys (c.859C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SCYL2 p.Arg287Cys (c.859C>T) in the general population?

SCYL2 p.Arg287Cys (c.859C>T) is very rare (popmax 0.00157%, nfe) (gnomAD).

What do computational predictors say about SCYL2 p.Arg287Cys (c.859C>T)?

AlphaMissense predicts likely benign (score 0.1806) — an in-silico prediction, not a clinical call.

SCYL2 p.Arg287Cys

c.859C>T · rs756262769 · VCV3158836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00157%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1806	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -10.02	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 7.7	GERP 1.9, phastCons 1
Overall
CADD	29.0	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 0.00157% European (non-Finnish) · 17/1,084,326 alleles

Filtering AF 0.000955% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000781%

Overall 0.00133% 18/1,351,720 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,780
European (non-Finnish)grpmax	0.00157%	63,784

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SCYL2
Protein: p.Arg287Cys
Coding: c.859C>T
MANE Select: NM_032963 · reported on NM_017988
dbSNP: rs756262769
Type: single nucleotide variant
Location: chr12:100313428 (GRCh38)
Structure: AlphaFold pLDDT 86.15 · 2 PDB

Full SCYL2 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

SCYL2 p.Arg287His Uncertain significance ★ ⚠ same residue
SCYL2 p.Leu478Pro Uncertain significance ★★ ⚠ same condition
SCYL2 p.Met321Val Uncertain significance ★★ ⚠ same condition
SCYL2 p.Ile615Met Likely benign ★★ same condition
SCYL2 p.Arg100Ter Pathogenic ★ same condition
SCYL2 p.Gln59Ter Pathogenic ★ same condition
SCYL2 c.1396-5T>C Uncertain significance ★ same condition
SCYL2 p.Ala191Thr 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/scyl2-p-arg287cys (accessed [today's date]).

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