Is TSHR p.Ile654Phe (c.1960A>T) pathogenic?

TSHR p.Ile654Phe (c.1960A>T) is classified Likely pathogenic in TSHR (ClinVar, Single submitter, 3 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.5932); Absent from gnomAD v4.1; Associated with hypothyroidism due to TSH receptor mutations.

What condition is associated with TSHR p.Ile654Phe (c.1960A>T)?

TSHR p.Ile654Phe (c.1960A>T) is associated with hypothyroidism due to TSH receptor mutations (ClinVar).

How common is TSHR p.Ile654Phe (c.1960A>T) in the general population?

TSHR p.Ile654Phe (c.1960A>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.

What do computational predictors say about TSHR p.Ile654Phe (c.1960A>T)?

AlphaMissense predicts likely pathogenic (score 0.5932) — an in-silico prediction, not a clinical call.

TSHR p.Ile654Phe

c.1960A>T · rs767239688 · VCV917861

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5932 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypothyroidism due to TSH receptor mutations

Computational evidence

Protein change
AlphaMissense	0.5932	likely pathogenic ✓ concordant with ClinVar
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -11.26	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 11	GERP 4.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

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.Ile654Phe
Coding: c.1960A>T
MANE Select: NM_000369
dbSNP: rs767239688
Type: single nucleotide variant
Location: chr14:81144018 (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

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

For Hypothyroidism due to TSH receptor mutations (Orphanet):

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

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-ile654phe (accessed [today's date]).

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