Is HPGD p.Ala140Pro (c.418G>C) pathogenic?

HPGD p.Ala140Pro (c.418G>C) is classified Pathogenic in HPGD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-11-10). AlphaMissense: likely pathogenic (0.9709); Ultra-rare (popmax 0.0476%, sas); Associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1.

How common is HPGD p.Ala140Pro (c.418G>C) in the general population?

HPGD p.Ala140Pro (c.418G>C) is ultra-rare (popmax 0.0476%, sas) (gnomAD).

What do computational predictors say about HPGD p.Ala140Pro (c.418G>C)?

AlphaMissense predicts likely pathogenic (score 0.9709) — an in-silico prediction, not a clinical call.

HPGD p.Ala140Pro

Q: What condition is associated with HPGD p.Ala140Pro (c.418G>C)?

HPGD p.Ala140Pro (c.418G>C) is associated with hypertrophic osteoarthropathy, primary, autosomal recessive, 1, cranio-osteoarthropathy (ClinVar).

c.418G>C · rs121434480 · VCV7917

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9709 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0476%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic osteoarthropathy, primary, autosomal recessive, 1

Computational evidence

Protein change
AlphaMissense	0.9709	likely pathogenic ✓ concordant with ClinVar · top 7% in HPGD
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -13.28	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 30 kb · p 0.32 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 0.0476% South Asian · 43/90,420 alleles

Filtering AF 0.0362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.00278% 44/1,580,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0476%	2,103
Remaining individualsnot grpmax-eligible	0.00163%	61,372

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.Ala140Pro
Coding: c.418G>C
MANE Select: NM_000860
dbSNP: rs121434480
Type: single nucleotide variant
Location: chr4:174508699 (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 140: a UniProt-annotated variant site (in coa; inactive); 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: cranio-osteoarthropathy

Similar variants

HPGD c.324+5G>A Pathogenic ★★ same condition
HPGD c.421+1G>T 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
HPGD p.Ser174Arg 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-ala140pro (accessed [today's date]).

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