Is HPGD p.Ala41fs (c.120del) pathogenic?

HPGD p.Ala41fs (c.120del) is classified Pathogenic in HPGD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-15). Ultra-rare (popmax 0.0121%, nfe); Associated with HPGD-related disorder.

What condition is associated with HPGD p.Ala41fs (c.120del)?

HPGD p.Ala41fs (c.120del) is associated with HPGD-related disorder, hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (ClinVar).

How common is HPGD p.Ala41fs (c.120del) in the general population?

HPGD p.Ala41fs (c.120del) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

HPGD p.Ala41fs

c.120del · rs769423339 · VCV2203595

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Conditions

HPGD-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 0.86, phastCons 1
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% European (non-Finnish) · 143/1,180,008 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00923% 149/1,614,072 alleles · ultra-rare exomes 140/1,461,844 · genomes 9/152,228 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,252
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00133%	74,956

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.Ala41fs
Coding: c.120del
MANE Select: NM_000860
dbSNP: rs769423339
Type: Deletion
Location: chr4:174522041 (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 41: an α-helix

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

Disease context

HPGD-related disorder

Also linked: hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Similar variants

HPGD p.Thr103fs Likely pathogenic ★★ same condition
HPGD p.Val78fs Likely pathogenic ★ same condition
HPGD p.Ala41Thr 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 p.Leu104fs Pathogenic ★★ 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-ala41fs (accessed [today's date]).

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