Is PGAP3 p.Leu59Val (c.175C>G) pathogenic?

PGAP3 p.Leu59Val (c.175C>G) is classified Conflicting classifications of pathogenicity in PGAP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.0972); Ultra-rare (popmax 0.0511%, sas); Associated with Inborn genetic diseases.

What condition is associated with PGAP3 p.Leu59Val (c.175C>G)?

PGAP3 p.Leu59Val (c.175C>G) is associated with Inborn genetic diseases, hyperphosphatasia with intellectual disability syndrome 4 (ClinVar).

How common is PGAP3 p.Leu59Val (c.175C>G) in the general population?

PGAP3 p.Leu59Val (c.175C>G) is ultra-rare (popmax 0.0511%, sas) (gnomAD).

What do computational predictors say about PGAP3 p.Leu59Val (c.175C>G)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

PGAP3 p.Leu59Val

c.175C>G · rs781433220 · VCV426823

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0511%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 0.084, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.63 · regional, not allelic
Overall
CADD	21.6	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 0.0511% South Asian · 39/76,276 alleles

Filtering AF 0.0384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.00493% 73/1,479,942 alleles · ultra-rare exomes 64/1,327,640 · genomes 9/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0511%	1,956
East Asian	0.0504%	1,982
Remaining individualsnot grpmax-eligible	0.0268%	3,736

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: PGAP3
Protein: p.Leu59Val
Coding: c.175C>G
MANE Select: NM_033419
dbSNP: rs781433220
Type: single nucleotide variant
Location: chr17:39687840 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.17

Full PGAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperphosphatasia with intellectual disability syndrome 4

Similar variants

PGAP3 c.558-10G>A Pathogenic/Likely pathogenic ★★ same condition
PGAP3 c.694+1G>A Pathogenic ★★ same condition
PGAP3 p.Asp305Gly Pathogenic/Likely pathogenic ★★ same condition
PGAP3 p.Gln89Ter Pathogenic ★★ same condition
PGAP3 p.Glu37Ter Pathogenic ★★ same condition
PGAP3 p.His284Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
PGAP3 p.His284Tyr Pathogenic/Likely pathogenic ★★ same condition
PGAP3 p.Pro105Gln Likely 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/pgap3-p-leu59val (accessed [today's date]).

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