Is BOLA1 p.Pro46Ser (c.136C>T) pathogenic?

BOLA1 p.Pro46Ser (c.136C>T) is classified Uncertain significance in BOLA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely pathogenic (0.7629); Ultra-rare (popmax 0.0133%, amr).

How common is BOLA1 p.Pro46Ser (c.136C>T) in the general population?

BOLA1 p.Pro46Ser (c.136C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about BOLA1 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

BOLA1 p.Pro46Ser

c.136C>T · rs782128050 · VCV2522341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic
REVEL	0.571	indeterminate
SaProt	LLR -12.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 410 bp · p 0.78 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0133% Admixed American · 8/59,996 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000496% 8/1,613,730 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: BOLA1
Protein: p.Pro46Ser
Coding: c.136C>T
MANE Select: NM_016074
dbSNP: rs782128050
Type: single nucleotide variant
Location: chr1:149900195 (GRCh38)
Gene constraint: LOEUF 1.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.40 · 1 PDB

Full BOLA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BOLA1 p.Ala103Val Uncertain significance ★ ⚠ same type
BOLA1 p.Ala108Thr Uncertain significance ★ ⚠ same type
BOLA1 p.Ala91Val Uncertain significance ★ ⚠ same type
BOLA1 p.Arg5Leu Uncertain significance ★ ⚠ same type
BOLA1 p.Arg69Leu Uncertain significance ★ ⚠ same type
BOLA1 p.Gln119His Uncertain significance ★ ⚠ same type
BOLA1 p.Glu65Asp Uncertain significance ★ ⚠ same type
BOLA1 p.Glu95Lys 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/bola1-p-pro46ser (accessed [today's date]).

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