Is BMPER p.Phe375Ser (c.1124T>C) pathogenic?

BMPER p.Phe375Ser (c.1124T>C) is classified Uncertain significance in BMPER (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with BMPER p.Phe375Ser (c.1124T>C)?

BMPER p.Phe375Ser (c.1124T>C) is associated with Inborn genetic diseases, diaphanospondylodysostosis (ClinVar).

How common is BMPER p.Phe375Ser (c.1124T>C) in the general population?

BMPER p.Phe375Ser (c.1124T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about BMPER p.Phe375Ser (c.1124T>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

BMPER p.Phe375Ser

c.1124T>C · rs756757241 · VCV1679888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 2% in BMPER
REVEL	0.918	moderately pathogenic-leaning
SaProt	LLR -12.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 248 kb · p 0.0046 · regional, not allelic
Overall
CADD	32.0	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000137% 2/1,461,894 alleles · very 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: BMPER
Protein: p.Phe375Ser
Coding: c.1124T>C
MANE Select: NM_001365308
dbSNP: rs756757241
Type: single nucleotide variant
Location: chr7:34078902 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.24
Residue 375: a disulfide bond; the vwfd domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: diaphanospondylodysostosis

Similar variants

BMPER p.Phe375= 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.Arg16Ser Uncertain significance ★★ ⚠ same condition
BMPER p.Arg332His 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-phe375ser (accessed [today's date]).

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