Is TSHR p.Val397= (c.1191G>T) pathogenic?

TSHR p.Val397= (c.1191G>T) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Absent from gnomAD v4.1; Associated with hypothyroidism due to TSH receptor mutations.

What condition is associated with TSHR p.Val397= (c.1191G>T)?

TSHR p.Val397= (c.1191G>T) is associated with hypothyroidism due to TSH receptor mutations, familial hyperthyroidism due to mutations in TSH receptor (ClinVar).

How common is TSHR p.Val397= (c.1191G>T) in the general population?

TSHR p.Val397= (c.1191G>T) is absent from gnomAD v4.1 (gnomAD).

How is Hypothyroidism due to TSH receptor mutations inherited?

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

TSHR p.Val397=

c.1191G>T · rs781406064 · VCV314696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hypothyroidism due to TSH receptor mutations

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 1	GERP 0.97, phastCons 1
Overall
CADD	4.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSHR
Protein: p.Val397=
Coding: c.1191G>T
MANE Select: NM_000369
dbSNP: rs781406064
Type: single nucleotide variant
Location: chr14:81143249 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 397: a β-strand

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

Disease context

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

Also linked: familial hyperthyroidism due to mutations in TSH receptor

For Hypothyroidism due to TSH receptor mutations (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TSHR p.Val397Met Uncertain significance ★ ⚠ same residue
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

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-val397 (accessed [today's date]).

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