Is PRDM16 p.Ser533Pro (c.1597T>C) pathogenic?

PRDM16 p.Ser533Pro (c.1597T>C) is classified Benign in PRDM16 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0446); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with left ventricular noncompaction 8.

What condition is associated with PRDM16 p.Ser533Pro (c.1597T>C)?

PRDM16 p.Ser533Pro (c.1597T>C) is associated with left ventricular noncompaction 8 (ClinVar).

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.Ser533Pro (c.1597T>C)?

AlphaMissense predicts likely benign (score 0.0446) — an in-silico prediction, not a clinical call.

PRDM16 p.Ser533Pro

Q: How common is PRDM16 p.Ser533Pro (c.1597T>C) in the general population?

PRDM16 p.Ser533Pro (c.1597T>C) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1597T>C · rs870124 · VCV227026

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0446 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

left ventricular noncompaction 8

Computational evidence

Protein change
AlphaMissense	0.0446	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -2.6, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 6,505 bp · p 0.39 · regional, not allelic
Overall
CADD	13.98	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 100% East Asian · 44,795/44,816 alleles

Filtering AF 99.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.9%

Overall 85.5% 1,377,126/1,611,306 alleles · common exomes 1,241,375/1,459,306 · genomes 135,751/152,000 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
African / African-American	97.2%	1
South Asian	94.7%	1
Finnishnot grpmax-eligible	91.4%	1
Admixed American	91.2%	1
Middle Eastern	90.4%	1
Remaining individualsnot grpmax-eligible	86.1%	1
Ashkenazi Jewishnot grpmax-eligible	85%	1
European (non-Finnish)	82.8%	1
Amishnot grpmax-eligible	77.5%	1

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.Ser533Pro
Coding: c.1597T>C
MANE Select: NM_022114
dbSNP: rs870124
Type: single nucleotide variant
Location: chr1:3411794 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.73 · 2 PDB
Residue 533: the 'disordered' region; a UniProt-annotated variant site (in)

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.Ser533= Benign/Likely benign ★★ same residue
PRDM16 p.Ser533Leu 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

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-ser533pro (accessed [today's date]).

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