Is HPGD p.Pro149= (c.447G>A) pathogenic?

HPGD p.Pro149= (c.447G>A) is classified Uncertain significance in HPGD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.00769%, sas); Associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1.

How common is HPGD p.Pro149= (c.447G>A) in the general population?

HPGD p.Pro149= (c.447G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

HPGD p.Pro149=

Q: What condition is associated with HPGD p.Pro149= (c.447G>A)?

HPGD p.Pro149= (c.447G>A) is associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1, isolated congenital digital clubbing (ClinVar).

c.447G>A · rs763652617 · VCV903589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -3.9
Overall
CADD	4.784	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,080 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000868% 14/1,613,730 alleles · very rare exomes 14/1,461,434 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
Admixed American	0.00167%	59,988
Finnishnot grpmax-eligible	0.00156%	63,990
European (non-Finnish)	0.000424%	235,946

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HPGD
Protein: p.Pro149=
Coding: c.447G>A
MANE Select: NM_000860
dbSNP: rs763652617
Type: single nucleotide variant
Location: chr4:174495599 (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

Also linked: isolated congenital digital clubbing

Similar variants

HPGD p.Pro149Arg Likely pathogenic 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-pro149 (accessed [today's date]).

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