Is TSHR p.Pro68Ser (c.202C>T) pathogenic?

TSHR p.Pro68Ser (c.202C>T) is classified Conflicting classifications of pathogenicity in TSHR (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-08-04). AlphaMissense: likely benign (0.2468); Rare (popmax 0.463%, mid); Associated with familial hyperthyroidism due to mutations in TSH receptor.

What condition is associated with TSHR p.Pro68Ser (c.202C>T)?

TSHR p.Pro68Ser (c.202C>T) is associated with familial hyperthyroidism due to mutations in TSH receptor, breast cancer, hypothyroidism due to TSH receptor mutations (ClinVar).

How common is TSHR p.Pro68Ser (c.202C>T) in the general population?

TSHR p.Pro68Ser (c.202C>T) is rare (popmax 0.463%, mid) (gnomAD).

What do computational predictors say about TSHR p.Pro68Ser (c.202C>T)?

AlphaMissense predicts likely benign (score 0.2468) — an in-silico prediction, not a clinical call.

TSHR p.Pro68Ser

Q: How is Familial hyperthyroidism due to mutations in TSH receptor inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.202C>T · rs142063461 · VCV437071

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2468 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.463%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hyperthyroidism due to mutations in TSH receptor

Computational evidence

Protein change
AlphaMissense	0.2468	likely benign
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -9.71	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	23.9	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 0.463% Middle Eastern · 28/6,044 alleles

Filtering AF 0.329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.284%

Overall 0.0359% 579/1,611,868 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.463%	216
Ashkenazi Jewishnot grpmax-eligible	0.271%	369
South Asian	0.118%	849
Admixed American	0.0651%	1,535
Remaining individualsnot grpmax-eligible	0.0545%	1,835
European (non-Finnish)	0.0242%	4,136
African / African-American	0.00667%	14,988
East Asian	0.00224%	44,704

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.Pro68Ser
Coding: c.202C>T
MANE Select: NM_000369
dbSNP: rs142063461
Type: single nucleotide variant
Location: chr14:81062179 (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

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

Also linked: breast cancer hypothyroidism due to TSH receptor mutations familial gestational hyperthyroidism

For Familial hyperthyroidism due to mutations in TSH receptor (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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-pro68ser (accessed [today's date]).

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