Is BYSL p.Arg63Trp (c.187C>T) pathogenic?

BYSL p.Arg63Trp (c.187C>T) is classified Uncertain significance in BYSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: ambiguous (0.451); Ultra-rare (popmax 0.0268%, eas).

How common is BYSL p.Arg63Trp (c.187C>T) in the general population?

BYSL p.Arg63Trp (c.187C>T) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about BYSL p.Arg63Trp (c.187C>T)?

AlphaMissense predicts ambiguous (score 0.451) — an in-silico prediction, not a clinical call.

BYSL p.Arg63Trp

c.187C>T · rs563253509 · VCV2539864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.451 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.451	ambiguous
REVEL	0.254	benign-leaning
SaProt	LLR -11.70	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.98, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 11 kb · p 0.019 · regional, not allelic
Overall
CADD	27.2	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 0.0268% East Asian · 12/44,842 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000806% 13/1,613,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,737
Middle Eastern	0.0166%	6,032

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: BYSL
Protein: p.Arg63Trp
Coding: c.187C>T
MANE Select: NM_004053
dbSNP: rs563253509
Type: single nucleotide variant
Location: chr6:41921749 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 78.24 · 13 PDB
Residue 63: the 'disordered' region; an α-helix

Full BYSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MED20 p.Met63Arg Uncertain significance ★ ⚠ same residue
MED20 p.Arg26Trp Uncertain significance ★★ ⚠ same type
MED20 p.Met30Val Uncertain significance ★★ ⚠ same type
BYSL p.Ala279Pro Uncertain significance ★ ⚠ same type
BYSL p.Ala28Glu Uncertain significance ★ ⚠ same type
BYSL p.Ala71Gly Uncertain significance ★ ⚠ same type
BYSL p.Arg131His Uncertain significance ★ ⚠ same type
BYSL p.Arg145His 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/bysl-p-arg63trp (accessed [today's date]).

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