Is PNPLA6 p.Pro44Ser (c.130C>T) pathogenic?

PNPLA6 p.Pro44Ser (c.130C>T) is classified Conflicting classifications of pathogenicity in PNPLA6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00187%, amr); Associated with Inborn genetic diseases.

What condition is associated with PNPLA6 p.Pro44Ser (c.130C>T)?

PNPLA6 p.Pro44Ser (c.130C>T) is associated with Inborn genetic diseases, hereditary spastic paraplegia 39 (ClinVar).

How common is PNPLA6 p.Pro44Ser (c.130C>T) in the general population?

PNPLA6 p.Pro44Ser (c.130C>T) is very rare (popmax 0.00187%, amr) (gnomAD).

What do computational predictors say about PNPLA6 p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

PNPLA6 p.Pro44Ser

c.130C>T · rs908461148 · VCV1630158

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 407 bp · p 0.97 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P53S vs ClinVar P44S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% Admixed American · 1/53,562 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000319% 5/1,569,038 alleles · very rare exomes 5/1,416,748 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00187%	53,562
African / African-American	0.00134%	74,706
European (non-Finnish)	0.000258%	387,720

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.Pro44Ser
Coding: c.130C>T
MANE Select: NM_001166114
dbSNP: rs908461148
Type: single nucleotide variant
Location: chr19:7535918 (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

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

Also linked: hereditary spastic paraplegia 39

Similar variants

PNPLA6 p.Pro44= Likely benign ★★ same residue
PNPLA6 p.Pro44Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro44ser (accessed [today's date]).

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