Is TFR2 p.Pro759= (c.2277C>T) pathogenic?

TFR2 p.Pro759= (c.2277C>T) is classified Likely benign in TFR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00407%, nfe); Associated with hereditary hemochromatosis.

What condition is associated with TFR2 p.Pro759= (c.2277C>T)?

TFR2 p.Pro759= (c.2277C>T) is associated with hereditary hemochromatosis, hemochromatosis type 3 (ClinVar).

How common is TFR2 p.Pro759= (c.2277C>T) in the general population?

TFR2 p.Pro759= (c.2277C>T) is very rare (popmax 0.00407%, nfe) (gnomAD).

TFR2 p.Pro759=

c.2277C>T · rs748376968 · VCV1126267

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Conditions

hereditary hemochromatosis

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 -3.1	GERP -9.1
Overall
CADD	0.866	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% European (non-Finnish) · 48/1,178,660 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00304% 49/1,610,508 alleles · very rare exomes 47/1,458,274 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,555
Admixed American	0.00168%	59,566

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: TFR2
Protein: p.Pro759=
Coding: c.2277C>T
MANE Select: NM_003227
dbSNP: rs748376968
Type: single nucleotide variant
Location: chr7:100620986 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.98

Full TFR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary hemochromatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemochromatosis type 3

Similar variants

TFR2 p.Pro759Leu Uncertain significance ⚠ same residue
TFR2 c.1473+1G>A Likely pathogenic ★★ same condition
TFR2 c.1474-1G>A Likely pathogenic ★★ same condition
TFR2 c.1606-2A>G Pathogenic ★★ same condition
TFR2 c.1606-8A>G Likely pathogenic ★★ same condition
TFR2 c.1767+1G>T Likely pathogenic ★★ same condition
TFR2 c.286+1G>T Likely pathogenic ★★ same condition
TFR2 c.286+2T>C Likely pathogenic ★★ 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/tfr2-p-pro759 (accessed [today's date]).

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