Is TG p.Ser2166= (c.6498T>C) pathogenic?

TG p.Ser2166= (c.6498T>C) is classified Conflicting classifications of pathogenicity in TG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-10). Ultra-rare (popmax 0.066%, mid); Associated with thyroid dyshormonogenesis 3.

What condition is associated with TG p.Ser2166= (c.6498T>C)?

TG p.Ser2166= (c.6498T>C) is associated with thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Ser2166= (c.6498T>C) in the general population?

TG p.Ser2166= (c.6498T>C) is ultra-rare (popmax 0.066%, mid) (gnomAD).

How is Familial thyroid dyshormonogenesis inherited?

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

TG p.Ser2166=

c.6498T>C · rs200367054 · VCV708930

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 0.066%, mid)

Conditions

thyroid dyshormonogenesis 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.38	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -4, phastCons 0.98
Overall
CADD	3.675	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00874% 141/1,614,102 alleles · ultra-rare exomes 127/1,461,734 · genomes 14/152,368 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,515
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,742
Admixed American	0.02%	5,003
Remaining individualsnot grpmax-eligible	0.0144%	6,945
European (non-Finnish)	0.0083%	12,041
African / African-American	0.00133%	75,076

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: TG
Protein: p.Ser2166=
Coding: c.6498T>C
MANE Select: NM_003235
dbSNP: rs200367054
Type: single nucleotide variant
Location: chr8:133013700 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)

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

Disease context

thyroid dyshormonogenesis 3 — 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

TG c.274+2T>G Pathogenic ★★ same condition
TG c.3634+1G>A Likely pathogenic ★★ same condition
TG c.5686+1G>A Pathogenic ★★ same condition
TG c.5686+1G>T Pathogenic ★★ same condition
TG c.638+5G>A Pathogenic/Likely pathogenic ★★ same condition
TG c.6782+1G>T Likely pathogenic ★★ same condition
TG c.7863-1G>A Likely pathogenic ★★ same condition
TG p.Arg1530Ter 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/tg-p-ser2166 (accessed [today's date]).

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