Is PNPLA3 p.Pro149= (c.447C>T) pathogenic?

PNPLA3 p.Pro149= (c.447C>T) is classified Benign in PNPLA3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-06-07). Common (popmax 50.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with NAFLD1.

What condition is associated with PNPLA3 p.Pro149= (c.447C>T)?

PNPLA3 p.Pro149= (c.447C>T) is associated with NAFLD1 (ClinVar).

PNPLA3 p.Pro149=

Q: How common is PNPLA3 p.Pro149= (c.447C>T) in the general population?

PNPLA3 p.Pro149= (c.447C>T) is common (popmax 50.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.447C>T · rs738408 · VCV341933

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 50.7%, amr) — too common for a highly-penetrant pathogenic allele

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 -3.7	GERP -1.5
Overall
CADD	0.284	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50.7% Admixed American · 30,376/59,884 alleles

Filtering AF 50.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.1%

Overall 23.2% 373,151/1,606,722 alleles · common exomes 338,558/1,455,024 · genomes 34,593/151,698 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	50.7%	2
East Asian	41.4%	2
Amishnot grpmax-eligible	27.3%	4
Middle Eastern	26.9%	4
Remaining individualsnot grpmax-eligible	23.1%	4
Finnishnot grpmax-eligible	22.6%	4
South Asian	22.5%	4
European (non-Finnish)	21.9%	5
Ashkenazi Jewishnot grpmax-eligible	21.7%	5
African / African-American	13.6%	7

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.Pro149=
Coding: c.447C>T
MANE Select: NM_025225
dbSNP: rs738408
Type: single nucleotide variant
Location: chr22:43928850 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.70
Residue 149: the pnpla domain

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-pro149 (accessed [today's date]).

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