Is PNPLA3 p.Pro403= (c.1209C>T) pathogenic?

PNPLA3 p.Pro403= (c.1209C>T) is classified Uncertain significance in PNPLA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Rare (popmax 0.253%, amr); Associated with NAFLD1.

What condition is associated with PNPLA3 p.Pro403= (c.1209C>T)?

PNPLA3 p.Pro403= (c.1209C>T) is associated with NAFLD1 (ClinVar).

How common is PNPLA3 p.Pro403= (c.1209C>T) in the general population?

PNPLA3 p.Pro403= (c.1209C>T) is rare (popmax 0.253%, amr) (gnomAD).

PNPLA3 p.Pro403=

c.1209C>T · rs184910573 · VCV341942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.253%, amr)

Conditions

NAFLD1

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 -4.5	GERP 0.79
Overall
CADD	4.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.253% Admixed American · 152/60,030 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.208%

Overall 0.0104% 168/1,614,072 alleles · rare exomes 147/1,461,742 · genomes 21/152,330 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.253%	395
East Asian	0.0111%	8,977
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.00133%	75,046
South Asian	0.0011%	91,078
European (non-Finnish)	0.000509%	196,653

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: PNPLA3
Protein: p.Pro403=
Coding: c.1209C>T
MANE Select: NM_025225
dbSNP: rs184910573
Type: single nucleotide variant
Location: chr22:43944787 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.70

Full PNPLA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NAFLD1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PNPLA3 c.697-4A>T Uncertain significance ★★ same condition
PNPLA3 p.Arg79Gln Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Asp136His Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Ile237Met Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Pro186His Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Ser364Cys Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Thr216Pro Uncertain significance ★★ ⚠ same condition
PNPLA3 p.Val162Met 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/pnpla3-p-pro403 (accessed [today's date]).

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