Is TIMP3 p.His83= (c.249T>C) pathogenic?

TIMP3 p.His83= (c.249T>C) is classified Benign in TIMP3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 84%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Sorsby fundus dystrophy.

What condition is associated with TIMP3 p.His83= (c.249T>C)?

TIMP3 p.His83= (c.249T>C) is associated with Sorsby fundus dystrophy, fundus dystrophy, pseudoinflammatory, recessive form (ClinVar).

How is Sorsby fundus dystrophy inherited?

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

TIMP3 p.His83=

Q: How common is TIMP3 p.His83= (c.249T>C) in the general population?

TIMP3 p.His83= (c.249T>C) is common (popmax 84%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.249T>C · rs9862 · VCV255943

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 84%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Sorsby fundus dystrophy

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.8	GERP 3.9, phastCons 1
Overall
CADD	12.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 84% African / African-American · 62,930/74,960 alleles

Filtering AF 83.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 83.2%

Overall 52.5% 846,048/1,612,676 alleles · common exomes 753,378/1,460,710 · genomes 92,670/151,966 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	84%	1
Amishnot grpmax-eligible	71.5%	1
Admixed American	69.3%	1
East Asian	63.9%	2
Middle Eastern	57.7%	2
Ashkenazi Jewishnot grpmax-eligible	54.7%	2
Remaining individualsnot grpmax-eligible	53.9%	2
South Asian	53.5%	2
European (non-Finnish)	49.4%	2
Finnishnot grpmax-eligible	43.1%	2

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.His83=
Coding: c.249T>C
MANE Select: NM_000362
dbSNP: rs9862
Type: single nucleotide variant
Location: chr22:32857293 (GRCh38)

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

Also linked: fundus dystrophy, pseudoinflammatory, recessive form

For Sorsby fundus dystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

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-his83 (accessed [today's date]).

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