Is TIMP3 p.Arg132= (c.396C>T) pathogenic?

TIMP3 p.Arg132= (c.396C>T) is classified Likely benign in TIMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Ultra-rare (popmax 0.036%, afr).

How common is TIMP3 p.Arg132= (c.396C>T) in the general population?

TIMP3 p.Arg132= (c.396C>T) is ultra-rare (popmax 0.036%, afr) (gnomAD).

TIMP3 p.Arg132=

c.396C>T · rs372535191 · VCV854976

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

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 2.2	GERP 2.9, phastCons 1
Overall
CADD	12.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/75,050 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.00248% 40/1,614,186 alleles · ultra-rare exomes 16/1,461,886 · genomes 24/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,780
Admixed American	0.0117%	8,575
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	8.47e-05%	1,180,030

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.Arg132=
Coding: c.396C>T
MANE Select: NM_000362
dbSNP: rs372535191
Type: single nucleotide variant
Location: chr22:32858096 (GRCh38)
Gene constraint: LOEUF 0.66 · pLI 0.46 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.49 · 1 PDB
Residue 132: the ntr domain; an α-helix; the 'mediates interaction with efemp1' region

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-arg132 (accessed [today's date]).

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