Is MMP13 p.Pro236Ser (c.706C>T) pathogenic?

MMP13 p.Pro236Ser (c.706C>T) is classified Uncertain significance in MMP13 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-01). AlphaMissense: ambiguous (0.4991); Very rare (popmax 0.000339%, nfe); Associated with spondyloepimetaphyseal dysplasia, Missouri type.

What condition is associated with MMP13 p.Pro236Ser (c.706C>T)?

MMP13 p.Pro236Ser (c.706C>T) is associated with spondyloepimetaphyseal dysplasia, Missouri type (ClinVar).

How common is MMP13 p.Pro236Ser (c.706C>T) in the general population?

MMP13 p.Pro236Ser (c.706C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MMP13 p.Pro236Ser (c.706C>T)?

AlphaMissense predicts ambiguous (score 0.4991) — an in-silico prediction, not a clinical call.

MMP13 p.Pro236Ser

Q: How is Spondyloepimetaphyseal dysplasia, Missouri type inherited?

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

c.706C>T · rs782443296 · VCV1679263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

spondyloepimetaphyseal dysplasia, Missouri type

Computational evidence

Protein change
AlphaMissense	0.4991	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -7.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 11 kb · p 0.75 · regional, not allelic
Overall
CADD	23.7	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 0.000339% European (non-Finnish) · 4/1,179,422 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,166 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: MMP13
Protein: p.Pro236Ser
Coding: c.706C>T
MANE Select: NM_002427
dbSNP: rs782443296
Type: single nucleotide variant
Location: chr11:102952105 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.00 · 49 PDB
Residue 236: the 'interaction with timp2' region; a β-strand

Full MMP13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondyloepimetaphyseal dysplasia, Missouri type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia, Missouri type (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

MMP13 p.Arg333Cys Uncertain significance ★★ ⚠ same condition
MMP13 p.Gly237Glu Uncertain significance ★★ ⚠ same condition
MMP13 p.Leu218Val Uncertain significance ★★ ⚠ same condition
MMP13 p.Pro273Arg Uncertain significance ★★ ⚠ same condition
MMP13 c.799+7C>T Benign/Likely benign ★★ same condition
MMP13 c.799+8G>A Benign ★★ same condition
MMP13 c.800-9C>T Benign ★★ same condition
MMP13 c.*314T>C Benign/Likely benign ★★ 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/mmp13-p-pro236ser (accessed [today's date]).

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