Is TSHR p.Pro119= (c.357T>A) pathogenic?

TSHR p.Pro119= (c.357T>A) is classified Conflicting classifications of pathogenicity in TSHR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). Rare (popmax 0.304%, nfe); Associated with familial hyperthyroidism due to mutations in TSH receptor.

What condition is associated with TSHR p.Pro119= (c.357T>A)?

TSHR p.Pro119= (c.357T>A) is associated with familial hyperthyroidism due to mutations in TSH receptor, hypothyroidism due to TSH receptor mutations (ClinVar).

How common is TSHR p.Pro119= (c.357T>A) in the general population?

TSHR p.Pro119= (c.357T>A) is rare (popmax 0.304%, nfe) (gnomAD).

TSHR p.Pro119=

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.357T>A · rs144084915 · VCV314692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.304%, nfe)

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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -2.4
Overall
CADD	5.492	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.304% European (non-Finnish) · 3,584/1,179,820 alleles

Filtering AF 0.295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.292%

Overall 0.254% 4,107/1,613,932 alleles · rare exomes 3,850/1,461,628 · genomes 257/152,304 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.304%	329
Remaining individualsnot grpmax-eligible	0.253%	396
South Asian	0.233%	430
Admixed American	0.155%	645
African / African-American	0.056%	1,786
Middle Eastern	0.0495%	2,020
Finnishnot grpmax-eligible	0.0203%	4,926
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,878

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.Pro119=
Coding: c.357T>A
MANE Select: NM_000369
dbSNP: rs144084915
Type: single nucleotide variant
Location: chr14:81087993 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB

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

Similar variants

TSHR c.881+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Ala553Thr Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Arg109Gln Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Arg450His Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Arg519Cys Pathogenic ★★ same condition
TSHR p.Arg519His Pathogenic/Likely pathogenic ★★ same condition
TSHR p.Cys390Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TSHR p.Gly132Arg 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/tshr-p-pro119 (accessed [today's date]).

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