Is TSHR p.Cys29Trp (c.87C>G) pathogenic?

TSHR p.Cys29Trp (c.87C>G) is classified Uncertain significance in TSHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-04). AlphaMissense: likely pathogenic (0.8767); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with TSHR p.Cys29Trp (c.87C>G)?

TSHR p.Cys29Trp (c.87C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TSHR p.Cys29Trp (c.87C>G) in the general population?

TSHR p.Cys29Trp (c.87C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about TSHR p.Cys29Trp (c.87C>G)?

AlphaMissense predicts likely pathogenic (score 0.8767) — an in-silico prediction, not a clinical call.

TSHR p.Cys29Trp

c.87C>G · rs777166186 · VCV2372295

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8767	likely pathogenic
REVEL	0.584	indeterminate
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2.3	GERP -1.5
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	18.71	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,614,066 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,415
East Asiangrpmax	0.00446%	22,444

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys29Trp
Coding: c.87C>G
MANE Select: NM_152446 · reported on NM_000369
dbSNP: rs777166186
Type: single nucleotide variant
Location: chr14:80955767 (GRCh38)

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

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-cys29trp (accessed [today's date]).

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