Is PNPLA6 p.Pro401= (c.1203C>A) pathogenic?

PNPLA6 p.Pro401= (c.1203C>A) is classified Benign/Likely benign in PNPLA6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). Rare (popmax 0.18%, eas); Associated with hereditary spastic paraplegia 39.

What condition is associated with PNPLA6 p.Pro401= (c.1203C>A)?

PNPLA6 p.Pro401= (c.1203C>A) is associated with hereditary spastic paraplegia 39 (ClinVar).

How common is PNPLA6 p.Pro401= (c.1203C>A) in the general population?

PNPLA6 p.Pro401= (c.1203C>A) is rare (popmax 0.18%, eas) (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.Pro401=

c.1203C>A · rs546470199 · VCV1170027

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.18%, eas)

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 -0.48	GERP -1.2
Overall
CADD	9.158	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.18% East Asian · 81/44,886 alleles

Filtering AF 0.149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.00889% 143/1,608,330 alleles · rare exomes 137/1,455,992 · genomes 6/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.18%	554
South Asian	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.0032%	31,234
European (non-Finnish)	0.00246%	40,687
Admixed American	0.00167%	60,008

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.Pro401=
Coding: c.1203C>A
MANE Select: NM_001166114
dbSNP: rs546470199
Type: single nucleotide variant
Location: chr19:7542018 (GRCh38)
Gene constraint: LOEUF 0.872 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.75
Residue 401: the 'disordered' 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 p.Pro401Thr Likely benign ★ same residue
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

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-pro401 (accessed [today's date]).

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