Is HPGD p.Gln52= (c.156G>A) pathogenic?

HPGD p.Gln52= (c.156G>A) is classified Benign in HPGD (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Common (popmax 42.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1.

HPGD p.Gln52=

Q: What condition is associated with HPGD p.Gln52= (c.156G>A)?

HPGD p.Gln52= (c.156G>A) is associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1, isolated congenital digital clubbing (ClinVar).

Q: How common is HPGD p.Gln52= (c.156G>A) in the general population?

HPGD p.Gln52= (c.156G>A) is common (popmax 42.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.156G>A · rs1050145 · VCV348204

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 42.9%, nfe) — too common for a highly-penetrant pathogenic allele

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 -0.12	GERP -2, phastCons 0.05
Overall
CADD	7.739	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42.9% European (non-Finnish) · 506,655/1,179,878 alleles

Filtering AF 42.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.8%

Overall 40.7% 656,735/1,613,832 alleles · common exomes 600,616/1,461,718 · genomes 56,119/152,114 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50.1%	2
European (non-Finnish)grpmax	42.9%	2
East Asian	42.2%	2
Finnishnot grpmax-eligible	40.9%	2
Remaining individualsnot grpmax-eligible	39.8%	3
Middle Eastern	37.6%	3
Ashkenazi Jewishnot grpmax-eligible	36%	3
Admixed American	31.7%	3
South Asian	29.9%	3
African / African-American	27.2%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln52=
Coding: c.156G>A
MANE Select: NM_000860
dbSNP: rs1050145
Type: single nucleotide variant
Location: chr4:174522005 (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 52: a turn

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 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
HPGD p.Gly114Glu Uncertain significance ★★ ⚠ same condition
HPGD p.Leu167Phe 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-gln52 (accessed [today's date]).

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