Is BYSL p.Arg8His (c.23G>A) pathogenic?

BYSL p.Arg8His (c.23G>A) is classified Uncertain significance in BYSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.2371); Ultra-rare (popmax 0.0167%, nfe).

How common is BYSL p.Arg8His (c.23G>A) in the general population?

BYSL p.Arg8His (c.23G>A) is ultra-rare (popmax 0.0167%, nfe) (gnomAD).

What do computational predictors say about BYSL p.Arg8His (c.23G>A)?

AlphaMissense predicts likely benign (score 0.2371) — an in-silico prediction, not a clinical call.

BYSL p.Arg8His

c.23G>A · rs143551764 · VCV2214382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2371	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 11 kb · p 0.019 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% European (non-Finnish) · 194/1,164,058 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.0132% 210/1,585,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)grpmax	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.0147%	6,788
Finnishnot grpmax-eligible	0.00636%	15,721
African / African-American	0.00271%	36,966

Amish 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: BYSL
Protein: p.Arg8His
Coding: c.23G>A
MANE Select: NM_004053
dbSNP: rs143551764
Type: single nucleotide variant
Location: chr6:41921585 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 78.24 · 13 PDB
Residue 8: the 'disordered' region

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

Similar variants

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
BYSL p.Arg189Gln 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-arg8his (accessed [today's date]).

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