Is PTH p.Ser23Pro (c.67T>C) pathogenic?

PTH p.Ser23Pro (c.67T>C) is classified Pathogenic in PTH (ClinVar, No assertion criteria, 1 submitter; last evaluated 1999-10-01). AlphaMissense: likely benign (0.194); Absent from gnomAD v4.1; Associated with hypoparathyroidism, familial isolated 1.

What condition is associated with PTH p.Ser23Pro (c.67T>C)?

PTH p.Ser23Pro (c.67T>C) is associated with hypoparathyroidism, familial isolated 1 (ClinVar).

How common is PTH p.Ser23Pro (c.67T>C) in the general population?

PTH p.Ser23Pro (c.67T>C) is absent from gnomAD v4.1 (gnomAD).

How is Familial isolated hypoparathyroidism inherited?

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

What do computational predictors say about PTH p.Ser23Pro (c.67T>C)?

AlphaMissense predicts likely benign (score 0.194) — an in-silico prediction, not a clinical call.

PTH p.Ser23Pro

c.67T>C · rs104894272 · VCV13758

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.194 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypoparathyroidism, familial isolated 1

Computational evidence

Protein change
AlphaMissense	0.194	likely benign ⚠ discordant with ClinVar
REVEL	0.588	indeterminate
SaProt	LLR -12.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -4.3, phastCons 0.011
Regional constraint	o/e 0.93	unconstrained · MANE · 447 bp · p 0.43 · regional, not allelic
Overall
CADD	17.15	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.Ser23Pro
Coding: c.67T>C
MANE Select: NM_000315
dbSNP: rs104894272
Type: single nucleotide variant
Location: chr11:13492789 (GRCh38)
Gene constraint: LOEUF 1.32 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 72.93 · 26 PDB
Residue 23: a UniProt-annotated variant site (in fih1; recessive form; might lead to inefficient processing of the precursor)

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

Disease context

hypoparathyroidism, familial isolated 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial isolated hypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

PTH p.Ser23= Benign ★ same residue
PTH c.-5-10G>A Benign/Likely benign ★★ same condition
PTH p.Arg83= Benign/Likely benign ★★ same condition
PTH p.Cys18Arg Likely pathogenic ★ 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

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-ser23pro (accessed [today's date]).

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