Is MMP14 p.Phe181Ser (c.542T>C) pathogenic?

MMP14 p.Phe181Ser (c.542T>C) is classified Uncertain significance in MMP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-28). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with Winchester syndrome.

What condition is associated with MMP14 p.Phe181Ser (c.542T>C)?

MMP14 p.Phe181Ser (c.542T>C) is associated with Winchester syndrome (ClinVar).

How common is MMP14 p.Phe181Ser (c.542T>C) in the general population?

MMP14 p.Phe181Ser (c.542T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MMP14 p.Phe181Ser (c.542T>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

MMP14 p.Phe181Ser

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

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

c.542T>C · rs1595014702 · VCV803007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Winchester syndrome

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 4% in MMP14
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MMP14
Protein: p.Phe181Ser
Coding: c.542T>C
MANE Select: NM_004995
dbSNP: rs1595014702
Type: single nucleotide variant
Location: chr14:22842571 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 12 PDB
Residue 181: a β-strand

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.Arg111His Pathogenic 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-phe181ser (accessed [today's date]).

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