Is PTH1R p.Ala487Pro (c.1459G>C) pathogenic?

PTH1R p.Ala487Pro (c.1459G>C) is classified Uncertain significance in PTH1R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). AlphaMissense: likely pathogenic (0.5944); Absent from gnomAD v4.1.

How common is PTH1R p.Ala487Pro (c.1459G>C) in the general population?

PTH1R p.Ala487Pro (c.1459G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTH1R p.Ala487Pro (c.1459G>C)?

AlphaMissense predicts likely pathogenic (score 0.5944) — an in-silico prediction, not a clinical call.

PTH1R p.Ala487Pro

c.1459G>C · rs2545053428 · VCV2854452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5944	likely pathogenic
REVEL	0.193	benign-leaning
SaProt	LLR -12.47	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 5,758 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	25.5	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: PTH1R
Protein: p.Ala487Pro
Coding: c.1459G>C
MANE Select: NM_000316
dbSNP: rs2545053428
Type: single nucleotide variant
Location: chr3:46903333 (GRCh38)
Gene constraint: LOEUF 0.667 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 72.29 · 48 PDB

Full PTH1R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTH1R p.Arg104Ter Pathogenic ★★ same type
PTH1R p.His223Arg Pathogenic ★★ same type
PTH1R c.543+4C>T Uncertain significance ★★ same type
PTH1R c.988+4C>T Uncertain significance ★★ same type
PTH1R p.Ala210Val Uncertain significance ★★ ⚠ same type
PTH1R p.Ala279Val Uncertain significance ★★ ⚠ same type
PTH1R p.Ala456Thr Uncertain significance ★★ ⚠ same type
PTH1R p.Ala46Thr Uncertain significance ★★ ⚠ same type

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/pth1r-p-ala487pro (accessed [today's date]).

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