Is PNPLA6 p.Pro512= (c.1536C>T) pathogenic?

PNPLA6 p.Pro512= (c.1536C>T) is classified Likely benign in PNPLA6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-09). Ultra-rare (popmax 0.0774%, afr); Associated with hereditary spastic paraplegia 39.

What condition is associated with PNPLA6 p.Pro512= (c.1536C>T)?

PNPLA6 p.Pro512= (c.1536C>T) is associated with hereditary spastic paraplegia 39 (ClinVar).

How common is PNPLA6 p.Pro512= (c.1536C>T) in the general population?

PNPLA6 p.Pro512= (c.1536C>T) is ultra-rare (popmax 0.0774%, afr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 39 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PNPLA6 p.Pro512=

c.1536C>T · rs140389368 · VCV698555

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0774%, afr)

Conditions

hereditary spastic paraplegia 39

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 0.066	GERP 0.26, phastCons 0.004
Overall
CADD	12.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0774% African / African-American · 58/74,936 alleles

Filtering AF 0.0614% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.0039% 63/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0774%	1,292
Remaining individualsnot grpmax-eligible	0.008%	12,497

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: PNPLA6
Protein: p.Pro512=
Coding: c.1536C>T
MANE Select: NM_001166114
dbSNP: rs140389368
Type: single nucleotide variant
Location: chr19:7543012 (GRCh38)
Gene constraint: LOEUF 0.872 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 512: the 'cnmp-binding domain 2' region

Full PNPLA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 39 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 39 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PNPLA6 c.2936+2T>C Likely pathogenic ★★ same condition
PNPLA6 c.315+1G>T Likely pathogenic ★★ same condition
PNPLA6 c.316-2A>T Pathogenic ★★ same condition
PNPLA6 c.3816+1G>A Likely pathogenic ★★ same condition
PNPLA6 p.Ala1102Thr Pathogenic/Likely pathogenic ★★ same condition
PNPLA6 p.Arg1089Gln Pathogenic ★★ same condition
PNPLA6 p.Arg1089Ter Pathogenic/Likely pathogenic ★★ same condition
PNPLA6 p.Arg1137Cys Pathogenic/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/pnpla6-p-pro512 (accessed [today's date]).

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