Is TIMP3 p.Ile8= (c.24C>A) pathogenic?

TIMP3 p.Ile8= (c.24C>A) is classified Likely benign in TIMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). Very rare (popmax 0.0006%, nfe).

How common is TIMP3 p.Ile8= (c.24C>A) in the general population?

TIMP3 p.Ile8= (c.24C>A) is very rare (popmax 0.0006%, nfe) (gnomAD).

TIMP3 p.Ile8=

c.24C>A · rs2046600499 · VCV1357033

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0006%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -11
Overall
CADD	5.753	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0006% European (non-Finnish) · 7/1,166,632 alleles

Filtering AF 0.00025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000444% 7/1,576,918 alleles · very rare exomes 7/1,424,654 · genomes 0/152,264 · joint denominator

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.Ile8=
Coding: c.24C>A
MANE Select: NM_000362
dbSNP: rs2046600499
Type: single nucleotide variant
Location: chr22:32802025 (GRCh38)
Gene constraint: LOEUF 0.66 · pLI 0.46 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.49 · 1 PDB

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

Similar variants

TIMP3 p.Gly173Ser Uncertain significance ★★ ⚠ same type
TIMP3 p.Leu104Pro Likely pathogenic ★ same type
TIMP3 p.Ser179Cys Pathogenic ★ same type
TIMP3 c.*1783A>G Uncertain significance ★ same type
TIMP3 c.*1802A>G Uncertain significance ★ same type
TIMP3 c.*1841C>A Uncertain significance ★ same type
TIMP3 c.*2152G>T Uncertain significance ★ same type
TIMP3 c.*2424G>A 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/timp3-p-ile8 (accessed [today's date]).

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