Is BYSL p.Arg406Trp (c.1216C>T) pathogenic?

BYSL p.Arg406Trp (c.1216C>T) is classified Uncertain significance in BYSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.232); Ultra-rare (popmax 0.0254%, afr).

How common is BYSL p.Arg406Trp (c.1216C>T) in the general population?

BYSL p.Arg406Trp (c.1216C>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about BYSL p.Arg406Trp (c.1216C>T)?

AlphaMissense predicts likely benign (score 0.232) — an in-silico prediction, not a clinical call.

BYSL p.Arg406Trp

c.1216C>T · VCV3262353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.232 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.232	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -12.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 11 kb · p 0.019 · regional, not allelic
Overall
CADD	33.0	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 0.0254% African / African-American · 19/74,948 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00217% 35/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,945
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00223%	44,894
European (non-Finnish)	0.00102%	98,337

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.Arg406Trp
Coding: c.1216C>T
MANE Select: NM_004053
Type: single nucleotide variant
Location: chr6:41932608 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 78.24 · 13 PDB
Residue 406: an α-helix

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

Similar variants

BYSL p.Arg406Gln 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-arg406trp (accessed [today's date]).

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