Is TPO p.Phe653fs (c.1955dup) pathogenic?

TPO p.Phe653fs (c.1955dup) is classified Pathogenic in TPO (ClinVar, Single submitter, 2 submitters; last evaluated 2018-08-03). Very rare (popmax 0.000593%, nfe); Associated with thyroid dyshormonogenesis 2A.

What condition is associated with TPO p.Phe653fs (c.1955dup)?

TPO p.Phe653fs (c.1955dup) is associated with thyroid dyshormonogenesis 2A (ClinVar).

How common is TPO p.Phe653fs (c.1955dup) in the general population?

TPO p.Phe653fs (c.1955dup) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Familial thyroid dyshormonogenesis inherited?

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

TPO p.Phe653fs

c.1955dup · rs1491142370 · VCV4054

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

thyroid dyshormonogenesis 2A

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 11 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP 0.9, phastCons 0.95
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,052 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,074 alleles · very rare

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: TPO
Protein: p.Phe653fs
Coding: c.1955dup
MANE Select: NM_001206744
dbSNP: rs1491142370
Type: Duplication
Location: chr2:1493987 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 653: a disulfide bond; a UniProt-annotated variant site (in tdh2a; uncertain significance)

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

Disease context

thyroid dyshormonogenesis 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thyroid dyshormonogenesis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

TPO p.Ala397fs Pathogenic ★★ same condition
TPO p.Glu17fs Pathogenic ★★ same condition
TPO p.Gly256fs Pathogenic ★ same condition
TPO c.482+1G>A Likely pathogenic ★★ same condition
TPO p.Arg665Gln Likely pathogenic ★★ ⚠ same condition
TPO p.Arg665Trp Pathogenic ★★ same condition
TPO p.Arg89Ter Pathogenic ★★ same condition
TPO p.Asn129fs Pathogenic/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/tpo-p-phe653fs (accessed [today's date]).

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