Is PNPLA6 p.Pro147= (c.441C>T) pathogenic?

PNPLA6 p.Pro147= (c.441C>T) is classified Likely benign in PNPLA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). Very rare (popmax 0.00052%, nfe); Associated with hereditary spastic paraplegia 39.

What condition is associated with PNPLA6 p.Pro147= (c.441C>T)?

PNPLA6 p.Pro147= (c.441C>T) is associated with hereditary spastic paraplegia 39 (ClinVar).

How common is PNPLA6 p.Pro147= (c.441C>T) in the general population?

PNPLA6 p.Pro147= (c.441C>T) is very rare (popmax 0.00052%, nfe) (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.Pro147=

c.441C>T · rs1238748321 · VCV1898698

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00052%, nfe)

Conditions

hereditary spastic paraplegia 39

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9	GERP -4.5
Overall
CADD	0.179	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00052% European (non-Finnish) · 6/1,154,342 alleles

Filtering AF 0.000187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000384% 6/1,561,804 alleles · very rare exomes 6/1,409,534 · genomes 0/152,270 · joint denominator

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.Pro147=
Coding: c.441C>T
MANE Select: NM_001166114
dbSNP: rs1238748321
Type: single nucleotide variant
Location: chr19:7539945 (GRCh38)
Gene constraint: LOEUF 0.872 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.75

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-pro147 (accessed [today's date]).

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