Is PRDM16 p.Pro499Ser (c.1495C>T) pathogenic?

PRDM16 p.Pro499Ser (c.1495C>T) is classified Uncertain significance in PRDM16 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-15). AlphaMissense: likely benign (0.1172); Very rare (popmax 0.00331%, sas); Associated with left ventricular noncompaction 8.

What condition is associated with PRDM16 p.Pro499Ser (c.1495C>T)?

PRDM16 p.Pro499Ser (c.1495C>T) is associated with left ventricular noncompaction 8 (ClinVar).

How common is PRDM16 p.Pro499Ser (c.1495C>T) in the general population?

PRDM16 p.Pro499Ser (c.1495C>T) is very rare (popmax 0.00331%, sas) (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.Pro499Ser (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.1172) — an in-silico prediction, not a clinical call.

PRDM16 p.Pro499Ser

c.1495C>T · rs1553176454 · VCV474406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

left ventricular noncompaction 8

Computational evidence

Protein change
AlphaMissense	0.1172	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -8.14	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 1.7	GERP -1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,505 bp · p 0.39 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% South Asian · 3/90,666 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000248% 4/1,610,284 alleles · very rare exomes 4/1,458,000 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,222
European (non-Finnish)	8.49e-05%	1,177,571

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.Pro499Ser
Coding: c.1495C>T
MANE Select: NM_022114
dbSNP: rs1553176454
Type: single nucleotide variant
Location: chr1:3411692 (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.Pro499fs 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-pro499ser (accessed [today's date]).

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