Is TSHR p.Trp520Ser (c.1559G>C) pathogenic?

TSHR p.Trp520Ser (c.1559G>C) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-05). AlphaMissense: likely pathogenic (0.7356); Very rare (popmax 0.00212%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TSHR p.Trp520Ser (c.1559G>C)?

TSHR p.Trp520Ser (c.1559G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TSHR p.Trp520Ser (c.1559G>C) in the general population?

TSHR p.Trp520Ser (c.1559G>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about TSHR p.Trp520Ser (c.1559G>C)?

AlphaMissense predicts likely pathogenic (score 0.7356) — an in-silico prediction, not a clinical call.

TSHR p.Trp520Ser

c.1559G>C · VCV3329577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7356	likely pathogenic
REVEL	0.762	pathogenic-leaning
SaProt	LLR -13.62	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 12	GERP 4.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	32.0	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 0.00212% European (non-Finnish) · 25/1,180,050 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,794 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,202
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Trp520Ser
Coding: c.1559G>C
MANE Select: NM_000369
Type: single nucleotide variant
Location: chr14:81143617 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 520: an α-helix; a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSHR p.Trp520Ter Pathogenic ★ same residue
TSHR p.Asp345Tyr Uncertain significance ★★ ⚠ same condition
TSHR p.Glu303Val Uncertain significance ★★ ⚠ same condition
TSHR p.Glu358Lys Uncertain significance ★★ ⚠ same condition
TSHR p.Glu758Lys Uncertain significance ★★ ⚠ same condition
TSHR p.Tyr444His Uncertain significance ★★ ⚠ same condition
TSHR c.468-3C>A Uncertain significance ★ same condition
TSHR p.Ala240Asp Uncertain significance ★ ⚠ 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-trp520ser (accessed [today's date]).

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