Is TG p.Arg321Ter (c.961C>T) pathogenic?

TG p.Arg321Ter (c.961C>T) is classified Pathogenic in TG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-06). Very rare (popmax 0.00223%, eas); Associated with autoimmune thyroid disease, susceptibility to, 3.

What condition is associated with TG p.Arg321Ter (c.961C>T)?

TG p.Arg321Ter (c.961C>T) is associated with autoimmune thyroid disease, susceptibility to, 3, thyroid dyshormonogenesis 3 (ClinVar).

How common is TG p.Arg321Ter (c.961C>T) in the general population?

TG p.Arg321Ter (c.961C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

TG p.Arg321Ter

c.961C>T · rs779043995 · VCV2910224

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

autoimmune thyroid disease, susceptibility to, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 48
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.051, phastCons 0.002
Overall
CADD	35.0	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 0.00223% East Asian · 1/44,874 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,210 alleles · very rare exomes 3/1,461,888 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
European (non-Finnish)	0.000169%	590,023

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.Arg321Ter
Coding: c.961C>T
MANE Select: NM_003235
dbSNP: rs779043995
Type: single nucleotide variant
Location: chr8:132882885 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 321: a β-strand; the thyroglobulin type-1 4 domain

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

Disease context

autoimmune thyroid disease, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thyroid dyshormonogenesis 3

Similar variants

TG p.Arg321Gln Uncertain significance ★ ⚠ same residue
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

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-arg321ter (accessed [today's date]).

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