Is PRDM16 p.Pro526= (c.1578G>A) pathogenic?

PRDM16 p.Pro526= (c.1578G>A) is classified Likely benign in PRDM16 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-05). Ultra-rare (popmax 0.0381%, nfe); Associated with left ventricular noncompaction 8.

What condition is associated with PRDM16 p.Pro526= (c.1578G>A)?

PRDM16 p.Pro526= (c.1578G>A) is associated with left ventricular noncompaction 8 (ClinVar).

How common is PRDM16 p.Pro526= (c.1578G>A) in the general population?

PRDM16 p.Pro526= (c.1578G>A) is ultra-rare (popmax 0.0381%, nfe) (gnomAD).

How is Left ventricular noncompaction inherited?

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

PRDM16 p.Pro526=

c.1578G>A · rs376747653 · VCV227861

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, nfe)

Conditions

left ventricular noncompaction 8

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 -8.8	GERP -4.9
Overall
CADD	0.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0381% European (non-Finnish) · 449/1,179,680 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.031% 499/1,611,396 alleles · ultra-rare exomes 476/1,459,482 · genomes 23/151,914 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0381%	2,627
Remaining individualsnot grpmax-eligible	0.0256%	3,904
African / African-American	0.0201%	4,987
East Asian	0.0178%	5,607
Admixed American	0.00834%	11,986
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,576
South Asian	0.0033%	30,343
Finnishnot grpmax-eligible	0.00322%	31,037

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.Pro526=
Coding: c.1578G>A
MANE Select: NM_022114
dbSNP: rs376747653
Type: single nucleotide variant
Location: chr1:3411775 (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.Pro526Leu 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
PRDM16 p.Ala1146Thr Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala175Val 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-pro526 (accessed [today's date]).

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