Is HPDL p.Arg43Pro (c.128G>C) pathogenic?

HPDL p.Arg43Pro (c.128G>C) is classified Uncertain significance in HPDL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.6852); Absent from gnomAD v4.1; Associated with spastic paraplegia 83, autosomal recessive.

What condition is associated with HPDL p.Arg43Pro (c.128G>C)?

HPDL p.Arg43Pro (c.128G>C) is associated with spastic paraplegia 83, autosomal recessive (ClinVar).

How common is HPDL p.Arg43Pro (c.128G>C) in the general population?

HPDL p.Arg43Pro (c.128G>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 83 inherited?

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

What do computational predictors say about HPDL p.Arg43Pro (c.128G>C)?

AlphaMissense predicts likely pathogenic (score 0.6852) — an in-silico prediction, not a clinical call.

HPDL p.Arg43Pro

c.128G>C · VCV4291094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6852 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spastic paraplegia 83, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.6852	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -10.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,112 bp · p 0.12 · regional, not allelic
Overall
CADD	22.6	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: HPDL
Protein: p.Arg43Pro
Coding: c.128G>C
MANE Select: NM_032756
Type: single nucleotide variant
Location: chr1:45327276 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.45
Residue 43: the voc 1 domain

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

Disease context

spastic paraplegia 83, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 83 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

HPDL p.Gly50Asp Pathogenic ★★ ⚠ same condition
HPDL p.Glu339= Likely benign ★★ same condition
HPDL p.Ala356Pro Likely pathogenic ★ same condition
HPDL p.Gln243Ter Likely pathogenic ★ same condition
HPDL p.Tyr288His Likely pathogenic ★ same condition
HPDL p.Gly272Ala Uncertain significance ★ ⚠ same condition
HPDL p.Met1Lys Uncertain significance ★ same condition
HPDL p.Pro283Ser 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/hpdl-p-arg43pro (accessed [today's date]).

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