Is PNPLA3 p.Pro446= (c.1338G>A) pathogenic?

PNPLA3 p.Pro446= (c.1338G>A) is classified Uncertain significance in PNPLA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0164%, mid); Associated with NAFLD1.

What condition is associated with PNPLA3 p.Pro446= (c.1338G>A)?

PNPLA3 p.Pro446= (c.1338G>A) is associated with NAFLD1 (ClinVar).

How common is PNPLA3 p.Pro446= (c.1338G>A) in the general population?

PNPLA3 p.Pro446= (c.1338G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

PNPLA3 p.Pro446=

c.1338G>A · rs753625728 · VCV903292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

NAFLD1

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 -0.4	GERP -7.7
Overall
CADD	2.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00564% 91/1,614,040 alleles · ultra-rare exomes 83/1,461,892 · genomes 8/152,148 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00669%	14,937
African / African-American	0.00534%	18,729
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Admixed American	0.00333%	30,000
East Asian	0.00223%	44,890
South Asian	0.0011%	91,086

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.Pro446=
Coding: c.1338G>A
MANE Select: NM_025225
dbSNP: rs753625728
Type: single nucleotide variant
Location: chr22:43946274 (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 p.Pro446Leu Uncertain significance ★ ⚠ same residue
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

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-pro446 (accessed [today's date]).

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