Is MBTPS2 p.Ser136= (c.408G>A) pathogenic?

MBTPS2 p.Ser136= (c.408G>A) is classified Benign/Likely benign in MBTPS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-19). Ultra-rare (popmax 0.0512%, amr); Associated with osteogenesis imperfecta.

What condition is associated with MBTPS2 p.Ser136= (c.408G>A)?

MBTPS2 p.Ser136= (c.408G>A) is associated with osteogenesis imperfecta (ClinVar).

How common is MBTPS2 p.Ser136= (c.408G>A) in the general population?

MBTPS2 p.Ser136= (c.408G>A) is ultra-rare (popmax 0.0512%, amr) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MBTPS2 p.Ser136=

c.408G>A · rs148895141 · VCV707859

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, amr)

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -4.4, phastCons 0.83
Overall
CADD	4.882	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0512% Admixed American · 23/44,921 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0394%

Overall 0.039% 468/1,200,023 alleles · ultra-rare exomes 418/1,090,565 · genomes 50/109,458 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.147%	681
Admixed Americangrpmax	0.0512%	1,953
European (non-Finnish)	0.0446%	2,245
African / African-American	0.0427%	2,345
Remaining individualsnot grpmax-eligible	0.0254%	3,942
Finnishnot grpmax-eligible	0.0131%	7,650
South Asian	0.00712%	14,055
East Asian	0.00595%	16,800

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MBTPS2
Protein: p.Ser136=
Coding: c.408G>A
MANE Select: NM_015884
dbSNP: rs148895141
Type: single nucleotide variant
Location: chrX:21845354 (GRCh38)
Structure: AlphaFold pLDDT 87.78

Full MBTPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

MBTPS2 p.Ser136Leu Uncertain significance ★ ⚠ same residue
MBTPS2 p.His413Tyr Benign/Likely benign ★★ same condition
MBTPS2 p.Pro153= Benign/Likely benign ★★ same condition
MBTPS2 c.671-10C>G Conflicting classifications of pathogenicity ★ same condition
MBTPS2 p.Ser136_Leu137insSerSer Uncertain significance ★ same residue
MBTPS2 p.Ser136_Leu137insSerSerSerSerSerSer Uncertain significance ★ same residue
MBTPS2 p.Ser136_Leu137insSerSerSerSerSerSerSerSerSerSerSerSer Uncertain significance ★ same residue
MBTPS2 p.Ser136del Uncertain significance ★ same residue

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/mbtps2-p-ser136 (accessed [today's date]).

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