Is MMP14 p.Arg111His (c.332G>A) pathogenic?

MMP14 p.Arg111His (c.332G>A) is classified Pathogenic in MMP14 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9773); Very rare (popmax 0.00223%, eas); Associated with Winchester syndrome.

What condition is associated with MMP14 p.Arg111His (c.332G>A)?

MMP14 p.Arg111His (c.332G>A) is associated with Winchester syndrome (ClinVar).

How common is MMP14 p.Arg111His (c.332G>A) in the general population?

MMP14 p.Arg111His (c.332G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MMP14 p.Arg111His (c.332G>A)?

AlphaMissense predicts likely pathogenic (score 0.9773) — an in-silico prediction, not a clinical call.

MMP14 p.Arg111His

Q: How is Multicentric osteolysis-nodulosis-arthropathy spectrum inherited?

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

c.332G>A · rs1284390443 · VCV3064215

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Winchester syndrome

Computational evidence

Protein change
AlphaMissense	0.9773	likely pathogenic ✓ concordant with ClinVar
REVEL	0.435	indeterminate
SaProt	LLR -11.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 1,799 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000372% 6/1,614,224 alleles · very rare exomes 6/1,461,886 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
Finnishnot grpmax-eligible	0.00156%	64,036
African / African-American	0.00133%	75,054
European (non-Finnish)	0.000254%	393,346

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: MMP14
Protein: p.Arg111His
Coding: c.332G>A
MANE Select: NM_004995
dbSNP: rs1284390443
Type: single nucleotide variant
Location: chr14:22841987 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 12 PDB

Full MMP14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Multicentric osteolysis-nodulosis-arthropathy spectrum (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MMP14 c.850+2C>T Uncertain significance ★★ same condition
MMP14 p.Ala147Val Uncertain significance ★ ⚠ same condition
MMP14 p.Phe181Ser Uncertain significance ★ ⚠ same condition
MMP14 p.Thr17Arg Pathogenic ⚠ same condition
MMP14 p.Ala165Asp Uncertain significance ★★ ⚠ same type
MMP14 p.Ala366Val Uncertain significance ★★ ⚠ same type
MMP14 p.Ala539Thr Uncertain significance ★★ ⚠ same type
MMP14 p.Ala539Val Uncertain significance ★★ ⚠ same type

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/mmp14-p-arg111his (accessed [today's date]).

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