Is HPGD p.Pro149Arg (c.446C>G) pathogenic?

HPGD p.Pro149Arg (c.446C>G) is classified Likely pathogenic in HPGD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-03-26). AlphaMissense: likely pathogenic (0.9692); Absent from gnomAD v4.1; Associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1.

What condition is associated with HPGD p.Pro149Arg (c.446C>G)?

HPGD p.Pro149Arg (c.446C>G) is associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (ClinVar).

How common is HPGD p.Pro149Arg (c.446C>G) in the general population?

HPGD p.Pro149Arg (c.446C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HPGD p.Pro149Arg (c.446C>G)?

AlphaMissense predicts likely pathogenic (score 0.9692) — an in-silico prediction, not a clinical call.

HPGD p.Pro149Arg

c.446C>G · rs375335006 · VCV599096

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9692 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Computational evidence

Protein change
AlphaMissense	0.9692	likely pathogenic ✓ concordant with ClinVar · top 8% in HPGD
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -13.18	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 30 kb · p 0.32 · regional, not allelic
Overall
CADD	27.5	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: HPGD
Protein: p.Pro149Arg
Coding: c.446C>G
MANE Select: NM_000860
dbSNP: rs375335006
Type: single nucleotide variant
Location: chr4:174495600 (GRCh38)
Gene constraint: LOEUF 1.28 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 6 PDB
Residue 149: an α-helix

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

Disease context

hypertrophic osteoarthropathy, primary, autosomal recessive, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPGD p.Pro149= Uncertain significance ★ same residue
HPGD p.Pro149Leu Uncertain significance ★★ ⚠ same residue
HPGD c.324+5G>A Pathogenic ★★ same condition
HPGD c.421+1G>T Pathogenic ★★ same condition
HPGD p.Ala140Pro Pathogenic ★★ same condition
HPGD p.Gln68Ter Pathogenic ★★ same condition
HPGD c.*157A>G Uncertain significance ★★ same condition
HPGD p.Asn95Ser 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/hpgd-p-pro149arg (accessed [today's date]).

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