Is PTH p.Cys18Arg (c.52T>C) pathogenic?

PTH p.Cys18Arg (c.52T>C) is classified Likely pathogenic in PTH (ClinVar, Single submitter, 2 submitters; last evaluated 2018-08-17). AlphaMissense: likely pathogenic (0.7132); Absent from gnomAD v4.1; Associated with PTH-related disorder.

What condition is associated with PTH p.Cys18Arg (c.52T>C)?

PTH p.Cys18Arg (c.52T>C) is associated with PTH-related disorder, hypoparathyroidism, familial isolated 1 (ClinVar).

How common is PTH p.Cys18Arg (c.52T>C) in the general population?

PTH p.Cys18Arg (c.52T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTH p.Cys18Arg (c.52T>C)?

AlphaMissense predicts likely pathogenic (score 0.7132) — an in-silico prediction, not a clinical call.

PTH p.Cys18Arg

c.52T>C · rs104894271 · VCV13756

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7132 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTH-related disorder

Computational evidence

Protein change
AlphaMissense	0.7132	likely pathogenic ✓ concordant with ClinVar · top 10% in PTH
REVEL	0.657	pathogenic-leaning
SaProt	LLR -10.22	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 5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 447 bp · p 0.43 · 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

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: PTH
Protein: p.Cys18Arg
Coding: c.52T>C
MANE Select: NM_000315
dbSNP: rs104894271
Type: single nucleotide variant
Location: chr11:13492804 (GRCh38)
Gene constraint: LOEUF 1.32 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 72.93 · 26 PDB
Residue 18: a UniProt-annotated variant site (in fih1; dominant form; leads to inefficient processing of the precursor; the expressed mutant hormone is trapped intracellularly in the endoplasmic reticulum resulting in apoptosis; mutant protein-expressing cells also show marked up-regulation of the endoplasmic reticulum stress-responsive hormones hspa5 and eif2ak3 and the proapoptotic transcription factor ddit3)

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

Disease context

PTH-related disorder

Also linked: hypoparathyroidism, familial isolated 1

Similar variants

PTH p.Arg56Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PTH c.-5-10G>A Benign/Likely benign ★★ same condition
PTH p.Arg83= Benign/Likely benign ★★ same condition
PTH p.Ser32Pro Likely pathogenic ★ ⚠ same condition
PTH p.Arg56His Uncertain significance ★ ⚠ same condition
PTH p.Gly43Glu Uncertain significance ★ same condition
PTH p.Val33Glu Uncertain significance ★ ⚠ same condition
PTH c.86+1G>C 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/pth-p-cys18arg (accessed [today's date]).

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