Is TIMP3 p.Ile205= (c.615C>T) pathogenic?

TIMP3 p.Ile205= (c.615C>T) is classified Likely benign in TIMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00254%, nfe); Associated with Sorsby fundus dystrophy.

What condition is associated with TIMP3 p.Ile205= (c.615C>T)?

TIMP3 p.Ile205= (c.615C>T) is associated with Sorsby fundus dystrophy (ClinVar).

How common is TIMP3 p.Ile205= (c.615C>T) in the general population?

TIMP3 p.Ile205= (c.615C>T) is very rare (popmax 0.00254%, nfe) (gnomAD).

How is Sorsby fundus dystrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TIMP3 p.Ile205=

c.615C>T · rs749317282 · VCV901719

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

Sorsby fundus dystrophy

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	GERP 3.1, phastCons 1
Overall
CADD	12.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,180,000 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,611,974 alleles · very rare exomes 31/1,459,654 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,333
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Ile205=
Coding: c.615C>T
MANE Select: NM_000362
dbSNP: rs749317282
Type: single nucleotide variant
Location: chr22:32859356 (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

Disease context

Sorsby fundus dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sorsby fundus dystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

TIMP3 p.Ser179Cys Pathogenic ★ same condition
TIMP3 c.*1783A>G Uncertain significance ★ same condition
TIMP3 c.*1802A>G Uncertain significance ★ same condition
TIMP3 c.*1841C>A Uncertain significance ★ same condition
TIMP3 c.*2152G>T Uncertain significance ★ same condition
TIMP3 c.*2424G>A Uncertain significance ★ same condition
TIMP3 c.*2763C>T Uncertain significance ★ same condition
TIMP3 c.*2817T>C Uncertain significance ★ same condition

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-ile205 (accessed [today's date]).

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