Is MMP14 p.Arg277Gln (c.830G>A) pathogenic?

MMP14 p.Arg277Gln (c.830G>A) is classified Uncertain significance in MMP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.118); Ultra-rare (popmax 0.0165%, mid).

How common is MMP14 p.Arg277Gln (c.830G>A) in the general population?

MMP14 p.Arg277Gln (c.830G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MMP14 p.Arg277Gln (c.830G>A)?

AlphaMissense predicts likely benign (score 0.118) — an in-silico prediction, not a clinical call.

MMP14 p.Arg277Gln

c.830G>A · rs142651327 · VCV2158580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.118	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -2.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,683 bp · p 0.003 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00316% 51/1,613,510 alleles · ultra-rare exomes 43/1,461,322 · genomes 8/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00667%	14,991
Remaining individualsnot grpmax-eligible	0.0064%	15,623
European (non-Finnish)	0.00331%	30,252
African / African-American	0.00267%	37,503
South Asian	0.0011%	91,040

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.Arg277Gln
Coding: c.830G>A
MANE Select: NM_004995
dbSNP: rs142651327
Type: single nucleotide variant
Location: chr14:22843398 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 12 PDB
Residue 277: an α-helix

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

Similar variants

MMP14 p.Arg277Pro Uncertain significance ★ ⚠ same residue
MMP14 p.Arg277Trp Uncertain significance ★ ⚠ same residue
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

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-arg277gln (accessed [today's date]).

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