Is PGAP1 p.Leu178= (c.534T>G) pathogenic?

PGAP1 p.Leu178= (c.534T>G) is classified Benign in PGAP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Common (popmax 7.57%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia.

What condition is associated with PGAP1 p.Leu178= (c.534T>G)?

PGAP1 p.Leu178= (c.534T>G) is associated with hereditary spastic paraplegia, intellectual disability, autosomal recessive 42 (ClinVar).

PGAP1 p.Leu178=

Q: How common is PGAP1 p.Leu178= (c.534T>G) in the general population?

PGAP1 p.Leu178= (c.534T>G) is common (popmax 7.57%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.534T>G · rs35444896 · VCV474993

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 7.57%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia

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 0.94	GERP 0.73, phastCons 0.98
Overall
CADD	5.645	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.57% African / African-American · 5,673/74,980 alleles

Filtering AF 7.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.33%

Overall 0.447% 7,207/1,613,862 alleles · common exomes 3,921/1,461,570 · genomes 3,286/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.57%	13
Admixed American	0.735%	136
Middle Eastern	0.71%	141
Remaining individualsnot grpmax-eligible	0.584%	171
Ashkenazi Jewishnot grpmax-eligible	0.071%	1,409
European (non-Finnish)	0.0547%	1,829
South Asian	0.0198%	5,059
Finnishnot grpmax-eligible	0.00156%	64,032

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: PGAP1
Protein: p.Leu178=
Coding: c.534T>G
MANE Select: NM_024989
dbSNP: rs35444896
Type: single nucleotide variant
Location: chr2:196912997 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 89.15

Full PGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, autosomal recessive 42

Similar variants

PGAP1 p.Gln466Ter Pathogenic ★★ same condition
PGAP1 p.Gln555Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Tyr758Ter Pathogenic/Likely pathogenic ★★ same condition
PGAP1 p.Ala298Thr Uncertain significance ★★ ⚠ same condition
PGAP1 p.Ala714Val Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg231Gln Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg250His Uncertain significance ★★ ⚠ same condition
PGAP1 p.Arg803Cys 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/pgap1-p-leu178 (accessed [today's date]).

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