Is BMPER p.Pro85Leu (c.254C>T) pathogenic?

BMPER p.Pro85Leu (c.254C>T) is classified Conflicting classifications of pathogenicity in BMPER (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-13). AlphaMissense: likely benign (0.0997); Rare (popmax 0.957%, mid); Associated with diaphanospondylodysostosis.

What condition is associated with BMPER p.Pro85Leu (c.254C>T)?

BMPER p.Pro85Leu (c.254C>T) is associated with diaphanospondylodysostosis (ClinVar).

How common is BMPER p.Pro85Leu (c.254C>T) in the general population?

BMPER p.Pro85Leu (c.254C>T) is rare (popmax 0.957%, mid) (gnomAD).

What do computational predictors say about BMPER p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely benign (score 0.0997) — an in-silico prediction, not a clinical call.

BMPER p.Pro85Leu

c.254C>T · rs142205105 · VCV360098

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0997 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.957%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

diaphanospondylodysostosis

Computational evidence

Protein change
AlphaMissense	0.0997	likely benign
REVEL	0.476	indeterminate
SaProt	LLR -11.30	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 248 kb · p 0.0046 · regional, not allelic
Overall
CADD	23.6	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 0.957% Middle Eastern · 58/6,060 alleles

Filtering AF 0.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.689%

Overall 0.0295% 476/1,614,152 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.957%	104
Admixed American	0.095%	1,053
Remaining individualsnot grpmax-eligible	0.0544%	1,838
European (non-Finnish)	0.0248%	4,027
South Asian	0.0176%	5,692
African / African-American	0.0173%	5,773
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921

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: BMPER
Protein: p.Pro85Leu
Coding: c.254C>T
MANE Select: NM_001365308
dbSNP: rs142205105
Type: single nucleotide variant
Location: chr7:33937323 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.24
Residue 85: the vwfc 1 domain

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

Disease context

diaphanospondylodysostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMPER p.Pro85= Likely benign ★ same residue
BMPER p.Arg241Ter Likely pathogenic ★★ same condition
BMPER p.Gln309Ter Pathogenic ★★ same condition
BMPER p.Ala39Ser Uncertain significance ★★ ⚠ same condition
BMPER p.Ala486Val Uncertain significance ★★ ⚠ same condition
BMPER p.Arg131Cys Uncertain significance ★★ ⚠ same condition
BMPER p.Arg505His Uncertain significance ★★ ⚠ same condition
BMPER p.Arg582Gln Uncertain significance ★★ ⚠ same condition

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/bmper-p-pro85leu (accessed [today's date]).

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