Is MMP14 p.Ala165Asp (c.494C>A) pathogenic?

MMP14 p.Ala165Asp (c.494C>A) is classified Uncertain significance in MMP14 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.1376); Ultra-rare (popmax 0.0964%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MMP14 p.Ala165Asp (c.494C>A)?

MMP14 p.Ala165Asp (c.494C>A) is associated with Inborn genetic diseases (ClinVar).

How common is MMP14 p.Ala165Asp (c.494C>A) in the general population?

MMP14 p.Ala165Asp (c.494C>A) is ultra-rare (popmax 0.0964%, nfe) (gnomAD).

What do computational predictors say about MMP14 p.Ala165Asp (c.494C>A)?

AlphaMissense predicts likely benign (score 0.1376) — an in-silico prediction, not a clinical call.

MMP14 p.Ala165Asp

c.494C>A · rs144960921 · VCV1423074

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1376 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0964%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1376	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.31	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 7.7	GERP -2.6, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 1,799 bp · p 5.5e-10 · regional, not allelic
Overall
CADD	23.4	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 0.0964% European (non-Finnish) · 1,138/1,180,014 alleles

Filtering AF 0.0917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0899%

Overall 0.0736% 1,188/1,614,026 alleles · ultra-rare exomes 1,129/1,461,788 · genomes 59/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0964%	1,037
Remaining individualsnot grpmax-eligible	0.0592%	1,689
African / African-American	0.0147%	6,812
Finnishnot grpmax-eligible	0.00312%	32,004

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.Ala165Asp
Coding: c.494C>A
MANE Select: NM_004995
dbSNP: rs144960921
Type: single nucleotide variant
Location: chr14:22842523 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.66 · 12 PDB
Residue 165: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MMP14 p.Ala165Val Uncertain significance ★ ⚠ same residue
MMP14 p.Ala366Val Uncertain significance ★★ ⚠ same condition
MMP14 p.Ala539Thr Uncertain significance ★★ ⚠ same condition
MMP14 p.Ala539Val Uncertain significance ★★ ⚠ same condition
MMP14 p.Arg168Cys Uncertain significance ★★ ⚠ same condition
MMP14 p.Arg343Trp Uncertain significance ★★ ⚠ same condition
MMP14 p.Arg362Gln Uncertain significance ★★ ⚠ same condition
MMP14 p.Arg513Gln Uncertain significance ★★ ⚠ 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/mmp14-p-ala165asp (accessed [today's date]).

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