Is TFR2 p.Ser64Pro (c.190T>C) pathogenic?

TFR2 p.Ser64Pro (c.190T>C) is classified Uncertain significance in TFR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-28). AlphaMissense: likely benign (0.0646); Absent from gnomAD v4.1; Associated with hemochromatosis type 3.

What condition is associated with TFR2 p.Ser64Pro (c.190T>C)?

TFR2 p.Ser64Pro (c.190T>C) is associated with hemochromatosis type 3 (ClinVar).

How common is TFR2 p.Ser64Pro (c.190T>C) in the general population?

TFR2 p.Ser64Pro (c.190T>C) is absent from gnomAD v4.1 (gnomAD).

How is TFR2-related hemochromatosis inherited?

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

What do computational predictors say about TFR2 p.Ser64Pro (c.190T>C)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

TFR2 p.Ser64Pro

c.190T>C · rs1639890217 · VCV910848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemochromatosis type 3

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 2.1, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	15.28	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TFR2
Protein: p.Ser64Pro
Coding: c.190T>C
MANE Select: NM_003227
dbSNP: rs1639890217
Type: single nucleotide variant
Location: chr7:100641072 (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 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
TFR2 c.287-2A>G 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-ser64pro (accessed [today's date]).

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