Is MMP14 p.Arg564His (c.1691G>A) pathogenic?

MMP14 p.Arg564His (c.1691G>A) is classified Uncertain significance in MMP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1234); Very rare (popmax 0.00407%, afr).

How common is MMP14 p.Arg564His (c.1691G>A) in the general population?

MMP14 p.Arg564His (c.1691G>A) is very rare (popmax 0.00407%, afr) (gnomAD).

What do computational predictors say about MMP14 p.Arg564His (c.1691G>A)?

AlphaMissense predicts likely benign (score 0.1234) — an in-silico prediction, not a clinical call.

MMP14 p.Arg564His

c.1691G>A · rs140676928 · VCV1925623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1234	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -5.22	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,683 bp · p 0.003 · regional, not allelic
Overall
CADD	31.0	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 0.00407% African / African-American · 3/73,758 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00266%

Overall 0.0034% 53/1,559,504 alleles · very rare exomes 46/1,407,346 · genomes 7/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00407%	24,586
European (non-Finnish)	0.00391%	25,569
Finnishnot grpmax-eligible	0.00332%	30,161
East Asian	0.00235%	42,566
Admixed American	0.00191%	52,490
South Asian	0.00117%	85,580

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.Arg564His
Coding: c.1691G>A
MANE Select: NM_004995
dbSNP: rs140676928
Type: single nucleotide variant
Location: chr14:22845981 (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

Similar variants

MMP14 p.Arg564Cys 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
MMP14 p.Arg343Trp 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-arg564his (accessed [today's date]).

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