Is HPD p.Ser73Pro (c.217T>C) pathogenic?

HPD p.Ser73Pro (c.217T>C) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.9902); Absent from gnomAD v4.1.

How common is HPD p.Ser73Pro (c.217T>C) in the general population?

HPD p.Ser73Pro (c.217T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPD p.Ser73Pro (c.217T>C)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

HPD p.Ser73Pro

c.217T>C · rs2500324648 · VCV3233598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 2% in HPD
REVEL	0.718	pathogenic-leaning
SaProt	LLR -15.85	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	33.0	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: HPD
Protein: p.Ser73Pro
Coding: c.217T>C
MANE Select: NM_002150
dbSNP: rs2500324648
Type: single nucleotide variant
Location: chr12:121856607 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 73: the voc 1 domain; a β-strand

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

Similar variants

HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same type
HPD p.Gln205Ter Pathogenic/Likely pathogenic ★★ same type
HPD p.Tyr160Cys Likely pathogenic ★★ same type
HPD c.198+3G>A Uncertain significance ★★ same type
HPD p.Ala230Thr Uncertain significance ★★ ⚠ same type
HPD p.Arg111Trp Uncertain significance ★★ ⚠ same type
HPD p.Arg119Gln Uncertain significance ★★ ⚠ same type
HPD p.Arg279Cys 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/hpd-p-ser73pro (accessed [today's date]).

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