Is TSHR p.Phe97Ser (c.290T>C) pathogenic?

TSHR p.Phe97Ser (c.290T>C) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely pathogenic (0.982); Very rare (popmax 8.48e-05%, nfe).

How common is TSHR p.Phe97Ser (c.290T>C) in the general population?

TSHR p.Phe97Ser (c.290T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TSHR p.Phe97Ser (c.290T>C)?

AlphaMissense predicts likely pathogenic (score 0.982) — an in-silico prediction, not a clinical call.

TSHR p.Phe97Ser

c.290T>C · rs1384603967 · VCV3252999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.982	likely pathogenic · top 5% in TSHR
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -13.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,440 alleles

Overall 6.84e-05% 1/1,460,976 alleles · very rare

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.Phe97Ser
Coding: c.290T>C
MANE Select: NM_000369
dbSNP: rs1384603967
Type: single nucleotide variant
Location: chr14:81068301 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 97: a β-strand

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

Similar variants

TSHR p.Phe97Val Likely pathogenic ★ same residue
TSHR c.881+1G>A Pathogenic/Likely pathogenic ★★ same type
TSHR c.881+1G>T Pathogenic/Likely pathogenic ★★ same type
TSHR p.Ala553Thr Pathogenic/Likely pathogenic ★★ same type
TSHR p.Arg109Gln Pathogenic/Likely pathogenic ★★ same type
TSHR p.Arg450His Pathogenic/Likely pathogenic ★★ same type
TSHR p.Arg519Cys Pathogenic ★★ same type
TSHR p.Arg519His Pathogenic/Likely pathogenic ★★ same type

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-phe97ser (accessed [today's date]).

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