Is TFR2 p.Pro640= (c.1920C>T) pathogenic?

TFR2 p.Pro640= (c.1920C>T) is classified Conflicting classifications of pathogenicity in TFR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0856%, sas); Associated with hemochromatosis type 3.

What condition is associated with TFR2 p.Pro640= (c.1920C>T)?

TFR2 p.Pro640= (c.1920C>T) is associated with hemochromatosis type 3, hereditary hemochromatosis (ClinVar).

How common is TFR2 p.Pro640= (c.1920C>T) in the general population?

TFR2 p.Pro640= (c.1920C>T) is ultra-rare (popmax 0.0856%, sas) (gnomAD).

How is TFR2-related hemochromatosis inherited?

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

TFR2 p.Pro640=

c.1920C>T · rs539909716 · VCV697146

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0856%, sas)

Conditions

hemochromatosis type 3

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 -0.002	GERP -3.3, phastCons 0.034
Overall
CADD	7.548	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0856% South Asian · 72/84,120 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0638%

Overall 0.00471% 73/1,551,310 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0856%	1,168
European (non-Finnish)	8.72e-05%	1,147,268

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.Pro640=
Coding: c.1920C>T
MANE Select: NM_003227
dbSNP: rs539909716
Type: single nucleotide variant
Location: chr7:100627339 (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

Also linked: hereditary hemochromatosis

For TFR2-related hemochromatosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

TFR2 p.Pro640His 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-pro640 (accessed [today's date]).

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