Is TFR2 p.Pro355fs (c.1044_1062dup) pathogenic?

TFR2 p.Pro355fs (c.10441062dup) is classified Likely pathogenic in TFR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). Very rare (popmax 0.00333%, amr); Associated with hemochromatosis type 3.

What condition is associated with TFR2 p.Pro355fs (c.1044_1062dup)?

TFR2 p.Pro355fs (c.1044_1062dup) is associated with hemochromatosis type 3 (ClinVar).

How common is TFR2 p.Pro355fs (c.1044_1062dup) in the general population?

TFR2 p.Pro355fs (c.1044_1062dup) is very rare (popmax 0.00333%, amr) (gnomAD).

How is TFR2-related hemochromatosis inherited?

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

TFR2 p.Pro355fs

c.1044_1062dup · VCV4062206

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

hemochromatosis type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 4.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,852 alleles · very rare exomes 2/1,461,700 · genomes 0/152,152 · 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: TFR2
Protein: p.Pro355fs
Coding: c.1044_1062dup
MANE Select: NM_003227
Type: Duplication
Location: chr7:100631849 (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

hemochromatosis type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For TFR2-related hemochromatosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

TFR2 p.Arg30fs Pathogenic ★★ same condition
TFR2 p.Asp746fs Pathogenic/Likely pathogenic ★★ same condition
TFR2 p.Glu150fs Likely pathogenic ★★ same condition
TFR2 p.Phe729fs Pathogenic/Likely pathogenic ★★ same condition
TFR2 c.1390+2dup Likely pathogenic ★ same condition
TFR2 p.Gly760fs Likely pathogenic ★ same condition
TFR2 p.His598fs Likely pathogenic ★ same condition
TFR2 p.Leu4fs 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-pro355fs (accessed [today's date]).

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