Is PRDM16 p.Phe126= (c.378C>T) pathogenic?

PRDM16 p.Phe126= (c.378C>T) is classified Likely benign in PRDM16 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-29). Ultra-rare (popmax 0.0216%, sas); Associated with left ventricular noncompaction 8.

What condition is associated with PRDM16 p.Phe126= (c.378C>T)?

PRDM16 p.Phe126= (c.378C>T) is associated with left ventricular noncompaction 8 (ClinVar).

How common is PRDM16 p.Phe126= (c.378C>T) in the general population?

PRDM16 p.Phe126= (c.378C>T) is ultra-rare (popmax 0.0216%, sas) (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.Phe126=

c.378C>T · rs774801289 · VCV1639936

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0216%, sas)

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 -4.2	GERP -4.3
Overall
CADD	6.776	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0216% South Asian · 17/78,770 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00222% 34/1,530,168 alleles · ultra-rare exomes 28/1,378,054 · genomes 6/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0216%	4,634
Middle Eastern	0.0176%	5,696
Admixed American	0.0105%	9,514
Remaining individualsnot grpmax-eligible	0.0017%	58,912
Finnishnot grpmax-eligible	0.00167%	60,004
African / African-American	0.00139%	72,080
European (non-Finnish)	0.000703%	142,185

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.Phe126=
Coding: c.378C>T
MANE Select: NM_022114
dbSNP: rs774801289
Type: single nucleotide variant
Location: chr1:3186465 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.73 · 2 PDB
Residue 126: the set domain; a β-strand

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 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
PRDM16 p.Ala34Val 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-phe126 (accessed [today's date]).

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