Is TIMP3 p.Pro200Ala (c.598C>G) pathogenic?

TIMP3 p.Pro200Ala (c.598C>G) is classified Uncertain significance in TIMP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-18). AlphaMissense: likely benign (0.0936); Very rare (popmax 0.00267%, afr).

How common is TIMP3 p.Pro200Ala (c.598C>G) in the general population?

TIMP3 p.Pro200Ala (c.598C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TIMP3 p.Pro200Ala (c.598C>G)?

AlphaMissense predicts likely benign (score 0.0936) — an in-silico prediction, not a clinical call.

TIMP3 p.Pro200Ala

c.598C>G · VCV3326197

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0936	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.8	GERP 3.2, phastCons 0.99
Regional constraint	o/e 0.74	unconstrained · MANE · 137 bp · p 0.036 · regional, not allelic
Overall
CADD	18.63	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 0.00267% African / African-American · 2/74,934 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,170 alleles · very rare exomes 6/1,460,978 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,467
European (non-Finnish)	0.000424%	236,005

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: TIMP3
Protein: p.Pro200Ala
Coding: c.598C>G
MANE Select: NM_000362
Type: single nucleotide variant
Location: chr22:32859339 (GRCh38)

Full TIMP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/timp3-p-pro200ala (accessed [today's date]).

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