Is HPGD p.Val145Ile (c.433G>A) pathogenic?

HPGD p.Val145Ile (c.433G>A) is classified Uncertain significance in HPGD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.14); Rare (popmax 0.123%, eas); Associated with isolated congenital digital clubbing.

What condition is associated with HPGD p.Val145Ile (c.433G>A)?

HPGD p.Val145Ile (c.433G>A) is associated with isolated congenital digital clubbing, hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (ClinVar).

How common is HPGD p.Val145Ile (c.433G>A) in the general population?

HPGD p.Val145Ile (c.433G>A) is rare (popmax 0.123%, eas) (gnomAD).

What do computational predictors say about HPGD p.Val145Ile (c.433G>A)?

AlphaMissense predicts likely benign (score 0.14) — an in-silico prediction, not a clinical call.

HPGD p.Val145Ile

c.433G>A · rs139715202 · VCV289387

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.14 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.123%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated congenital digital clubbing

Computational evidence

Protein change
AlphaMissense	0.14	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.1, phastCons 0.32
Regional constraint	o/e 1.06	unconstrained · MANE · 30 kb · p 0.32 · regional, not allelic
Overall
CADD	15.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.123% East Asian · 55/44,864 alleles

Filtering AF 0.0967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0874%

Overall 0.029% 467/1,612,712 alleles · rare exomes 428/1,460,418 · genomes 39/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.123%	816
Middle Eastern	0.0825%	1,212
Admixed American	0.07%	1,428
Remaining individualsnot grpmax-eligible	0.0464%	2,154
European (non-Finnish)	0.0262%	3,815
South Asian	0.0187%	5,357
African / African-American	0.008%	12,498
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,797
Finnishnot grpmax-eligible	0.00313%	31,983

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.Val145Ile
Coding: c.433G>A
MANE Select: NM_000860
dbSNP: rs139715202
Type: single nucleotide variant
Location: chr4:174495613 (GRCh38)
Gene constraint: LOEUF 1.28 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.82 · 6 PDB

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

Disease context

isolated congenital digital clubbing — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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-val145ile (accessed [today's date]).

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