Is BMPER p.Pro222Ser (c.664C>T) pathogenic?

BMPER p.Pro222Ser (c.664C>T) is classified Conflicting classifications of pathogenicity in BMPER (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.2937); Rare (popmax 0.356%, afr); Associated with diaphanospondylodysostosis.

What condition is associated with BMPER p.Pro222Ser (c.664C>T)?

BMPER p.Pro222Ser (c.664C>T) is associated with diaphanospondylodysostosis (ClinVar).

How common is BMPER p.Pro222Ser (c.664C>T) in the general population?

BMPER p.Pro222Ser (c.664C>T) is rare (popmax 0.356%, afr) (gnomAD).

What do computational predictors say about BMPER p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely benign (score 0.2937) — an in-silico prediction, not a clinical call.

BMPER p.Pro222Ser

c.664C>T · rs148867097 · VCV911115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2937 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.356%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

diaphanospondylodysostosis

Computational evidence

Protein change
AlphaMissense	0.2937	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 248 kb · p 0.0046 · regional, not allelic
Overall
CADD	27.1	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 0.356% African / African-American · 267/74,992 alleles

Filtering AF 0.321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.307%

Overall 0.0188% 304/1,613,698 alleles · rare exomes 144/1,461,478 · genomes 160/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.356%	281
Remaining individualsnot grpmax-eligible	0.0288%	3,472
Admixed American	0.0233%	4,287
Middle Eastern	0.0165%	6,056
South Asian	0.0011%	91,070
European (non-Finnish)	0.000254%	393,224

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.Pro222Ser
Coding: c.664C>T
MANE Select: NM_001365308
dbSNP: rs148867097
Type: single nucleotide variant
Location: chr7:34046393 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.24
Residue 222: the vwfc 3 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.Pro222= 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-pro222ser (accessed [today's date]).

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