Is TSHR p.Pro162Ser (c.484C>T) pathogenic?

TSHR p.Pro162Ser (c.484C>T) is classified Conflicting classifications of pathogenicity in TSHR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-15). AlphaMissense: likely benign (0.2979); Ultra-rare (popmax 0.0165%, mid); Associated with hypothyroidism due to TSH receptor mutations.

What condition is associated with TSHR p.Pro162Ser (c.484C>T)?

TSHR p.Pro162Ser (c.484C>T) is associated with hypothyroidism due to TSH receptor mutations (ClinVar).

How common is TSHR p.Pro162Ser (c.484C>T) in the general population?

TSHR p.Pro162Ser (c.484C>T) is ultra-rare (popmax 0.0165%, mid) (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.Pro162Ser (c.484C>T)?

AlphaMissense predicts likely benign (score 0.2979) — an in-silico prediction, not a clinical call.

TSHR p.Pro162Ser

c.484C>T · rs121908863 · VCV623326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypothyroidism due to TSH receptor mutations

Computational evidence

Protein change
AlphaMissense	0.2979	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	GERP 0.38, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,810 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.000339%	294,994

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.Pro162Ser
Coding: c.484C>T
dbSNP: rs121908863
Type: single nucleotide variant
Location: chr14:81092547 (GRCh38)

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

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-pro162ser (accessed [today's date]).

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