Is BYSL p.Pro127Ala (c.379C>G) pathogenic?

BYSL p.Pro127Ala (c.379C>G) is classified Uncertain significance in BYSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.062); Ultra-rare (popmax 0.02%, amr).

How common is BYSL p.Pro127Ala (c.379C>G) in the general population?

BYSL p.Pro127Ala (c.379C>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about BYSL p.Pro127Ala (c.379C>G)?

AlphaMissense predicts likely benign (score 0.062) — an in-silico prediction, not a clinical call.

BYSL p.Pro127Ala

c.379C>G · VCV3483331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.062	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.13	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 5.1	GERP -0.29, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 11 kb · p 0.019 · regional, not allelic
Overall
CADD	18.49	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 0.02% Admixed American · 12/59,984 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000744% 12/1,613,950 alleles · ultra-rare

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.Pro127Ala
Coding: c.379C>G
MANE Select: NM_004053
Type: single nucleotide variant
Location: chr6:41927484 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 78.24 · 13 PDB

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-pro127ala (accessed [today's date]).

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