Is MMP14 p.Arg90His (c.269G>A) pathogenic?

MMP14 p.Arg90His (c.269G>A) is classified Uncertain significance in MMP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.2633); Ultra-rare (popmax 0.0296%, sas).

How common is MMP14 p.Arg90His (c.269G>A) in the general population?

MMP14 p.Arg90His (c.269G>A) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about MMP14 p.Arg90His (c.269G>A)?

AlphaMissense predicts likely benign (score 0.2633) — an in-silico prediction, not a clinical call.

MMP14 p.Arg90His

c.269G>A · rs778695115 · VCV1378978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2633	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.3, 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

Grpmax group 0.0296% South Asian · 27/91,082 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00409% 66/1,614,054 alleles · ultra-rare exomes 61/1,461,888 · genomes 5/152,166 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
Admixed American	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.0022%	45,386

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.Arg90His
Coding: c.269G>A
MANE Select: NM_004995
dbSNP: rs778695115
Type: single nucleotide variant
Location: chr14:22841924 (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 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-arg90his (accessed [today's date]).

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