Is TSHR p.Arg255= (c.765A>G) pathogenic?

TSHR p.Arg255= (c.765A>G) is classified Conflicting classifications of pathogenicity in TSHR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-23). Very rare (popmax 0.00333%, amr); Associated with familial hyperthyroidism due to mutations in TSH receptor.

What condition is associated with TSHR p.Arg255= (c.765A>G)?

TSHR p.Arg255= (c.765A>G) is associated with familial hyperthyroidism due to mutations in TSH receptor, hypothyroidism due to TSH receptor mutations (ClinVar).

How common is TSHR p.Arg255= (c.765A>G) in the general population?

TSHR p.Arg255= (c.765A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

TSHR p.Arg255=

Q: How is Familial hyperthyroidism due to mutations in TSH receptor inherited?

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

c.765A>G · rs777128238 · VCV726776

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

familial hyperthyroidism due to mutations in TSH receptor

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.6	GERP -3.8, phastCons 1
Overall
CADD	7.714	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,014 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,614,112 alleles · very rare exomes 22/1,461,892 · genomes 8/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,007
European (non-Finnish)	0.00229%	43,705
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: TSHR
Protein: p.Arg255=
Coding: c.765A>G
MANE Select: NM_000369
dbSNP: rs777128238
Type: single nucleotide variant
Location: chr14:81139751 (GRCh38)

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

Disease context

familial hyperthyroidism due to mutations in TSH receptor — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypothyroidism due to TSH receptor mutations

For Familial hyperthyroidism due to mutations in TSH receptor (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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/tshr-p-arg255 (accessed [today's date]).

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