Is PRDM16 p.Arg288Pro (c.863G>C) pathogenic?

PRDM16 p.Arg288Pro (c.863G>C) is classified Uncertain significance in PRDM16 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-20). AlphaMissense: likely pathogenic (0.9548); Very rare (popmax 0.000848%, nfe); Associated with left ventricular noncompaction 8.

What condition is associated with PRDM16 p.Arg288Pro (c.863G>C)?

PRDM16 p.Arg288Pro (c.863G>C) is associated with left ventricular noncompaction 8 (ClinVar).

How common is PRDM16 p.Arg288Pro (c.863G>C) in the general population?

PRDM16 p.Arg288Pro (c.863G>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

How is Left ventricular noncompaction inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PRDM16 p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.9548) — an in-silico prediction, not a clinical call.

PRDM16 p.Arg288Pro

c.863G>C · rs141374404 · VCV849151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

left ventricular noncompaction 8

Computational evidence

Protein change
AlphaMissense	0.9548	likely pathogenic
REVEL	0.179	moderately benign-leaning
SaProt	LLR -15.32	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 336 kb · p 0.018 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,178,854 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000621% 10/1,609,472 alleles · very rare exomes 10/1,458,868 · genomes 0/150,604 · joint denominator

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: PRDM16
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_022114
dbSNP: rs141374404
Type: single nucleotide variant
Location: chr1:3402977 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.73 · 2 PDB

Full PRDM16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

left ventricular noncompaction 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Left ventricular noncompaction (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages

Similar variants

PRDM16 p.Arg288Gln Uncertain significance ★★ ⚠ same residue
PRDM16 p.Arg288Gly Uncertain significance ★★ ⚠ same residue
PRDM16 p.Arg288Trp Uncertain significance ★ ⚠ same residue
PRDM16 c.388-2A>G Uncertain significance ★★ same condition
PRDM16 p.Ala1035Ser Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala106Thr Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala1096Thr Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala1096Val 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/prdm16-p-arg288pro (accessed [today's date]).

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