Is MMP14 p.Pro8Ser (c.22C>T) pathogenic?

MMP14 p.Pro8Ser (c.22C>T) is classified Benign in MMP14 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.067); Common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MMP14 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

MMP14 p.Pro8Ser

Q: How common is MMP14 p.Pro8Ser (c.22C>T) in the general population?

MMP14 p.Pro8Ser (c.22C>T) is common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.22C>T · rs1042703 · VCV1279198

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.1	GERP -4.2, phastCons 0.37
Regional constraint	o/e 0.92	unconstrained · MANE · 4,675 bp · p 0.59 · regional, not allelic
Overall
CADD	11.24	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 99.9% East Asian · 44,745/44,804 alleles

Filtering AF 99.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.8%

Overall 84.4% 1,360,146/1,611,232 alleles · common exomes 1,231,649/1,459,308 · genomes 128,497/151,924 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	99.9%	1
Finnishnot grpmax-eligible	87.9%	1
Admixed American	87.4%	1
Remaining individualsnot grpmax-eligible	84.5%	1
European (non-Finnish)	84.2%	1
African / African-American	83.3%	1
Ashkenazi Jewishnot grpmax-eligible	83.2%	1
Middle Eastern	82%	1
South Asian	77%	1
Amishnot grpmax-eligible	66.8%	1

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_004995
dbSNP: rs1042703
Type: single nucleotide variant
Location: chr14:22836839 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 12 PDB
Residue 8: a UniProt-annotated variant site (in)

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

Similar variants

MMP14 c.850+2C>T Uncertain significance ★★ same type
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
MMP14 p.Arg168Cys Uncertain significance ★★ ⚠ same type
MMP14 p.Arg343Trp Uncertain significance ★★ ⚠ same type
MMP14 p.Arg362Gln 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-pro8ser (accessed [today's date]).

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