Is TSHR p.Ser442Arg (c.1326C>A) pathogenic?

TSHR p.Ser442Arg (c.1326C>A) is classified Uncertain significance in TSHR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.9399); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TSHR p.Ser442Arg (c.1326C>A)?

TSHR p.Ser442Arg (c.1326C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TSHR p.Ser442Arg (c.1326C>A) in the general population?

TSHR p.Ser442Arg (c.1326C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSHR p.Ser442Arg (c.1326C>A)?

AlphaMissense predicts likely pathogenic (score 0.9399) — an in-silico prediction, not a clinical call.

TSHR p.Ser442Arg

c.1326C>A · VCV4838463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9399 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9399	likely pathogenic
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -11.91	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 -0.23	GERP 1.1, phastCons 0.21
Regional constraint	o/e 0.93	unconstrained · MANE · 189 kb · p 0.032 · regional, not allelic
Overall
CADD	20.8	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

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.Ser442Arg
Coding: c.1326C>A
MANE Select: NM_000369
Type: single nucleotide variant
Location: chr14:81143384 (GRCh38)
Gene constraint: LOEUF 1.012 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 9 PDB
Residue 442: a β-strand

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.Ser442Asn Uncertain significance ★ 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-ser442arg (accessed [today's date]).

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