Is PRDM16 p.Phe727Val (c.2179T>G) pathogenic?

PRDM16 p.Phe727Val (c.2179T>G) is classified Uncertain significance in PRDM16 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4114); Ultra-rare (popmax 0.0567%, amr); Associated with Inborn genetic diseases.

What condition is associated with PRDM16 p.Phe727Val (c.2179T>G)?

PRDM16 p.Phe727Val (c.2179T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PRDM16 p.Phe727Val (c.2179T>G) in the general population?

PRDM16 p.Phe727Val (c.2179T>G) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about PRDM16 p.Phe727Val (c.2179T>G)?

AlphaMissense predicts ambiguous (score 0.4114) — an in-silico prediction, not a clinical call.

PRDM16 p.Phe727Val

c.2179T>G · VCV4143914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4114	ambiguous
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,505 bp · p 0.39 · regional, not allelic
Overall
CADD	22.2	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 0.0567% Admixed American · 34/60,004 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00217% 35/1,613,360 alleles · ultra-rare exomes 8/1,461,176 · genomes 27/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Phe727Val
Coding: c.2179T>G
MANE Select: NM_022114
Type: single nucleotide variant
Location: chr1:3412376 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.73 · 2 PDB
Residue 727: the 'interaction with ctbp1, ctbp2 and znf516' region; a UniProt-annotated variant site (in lvnc8)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRDM16 p.Ala175Val Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala481Thr Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala572Asp Uncertain significance ★★ ⚠ same condition
PRDM16 p.Ala746Thr Uncertain significance ★★ ⚠ same condition
PRDM16 p.Arg1173Gln Uncertain significance ★★ ⚠ same condition
PRDM16 p.Arg118Trp Uncertain significance ★★ ⚠ same condition
PRDM16 p.Arg247His Uncertain significance ★★ ⚠ same condition
PRDM16 p.Arg26Trp 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-phe727val (accessed [today's date]).

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