Is PRDM16 p.Pro1108Arg (c.3323C>G) pathogenic?

PRDM16 p.Pro1108Arg (c.3323C>G) is classified Uncertain significance in PRDM16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.0966); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with PRDM16 p.Pro1108Arg (c.3323C>G)?

PRDM16 p.Pro1108Arg (c.3323C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PRDM16 p.Pro1108Arg (c.3323C>G) in the general population?

PRDM16 p.Pro1108Arg (c.3323C>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about PRDM16 p.Pro1108Arg (c.3323C>G)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

PRDM16 p.Pro1108Arg

c.3323C>G · VCV3309772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.73	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 3.3	GERP 0.49, phastCons 0.91
Regional constraint	o/e 0.91	unconstrained · MANE · 8,141 bp · p 0.088 · regional, not allelic
Overall
CADD	20.1	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 0.004% African / African-American · 3/74,912 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,966 alleles · very rare exomes 2/1,461,774 · genomes 1/152,192 · joint denominator

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.Pro1108Arg
Coding: c.3323C>G
MANE Select: NM_022114
Type: single nucleotide variant
Location: chr1:3430910 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.73 · 2 PDB
Residue 1108: the 'mediates interaction with ski and regulation of tgf-beta signaling' region; the 'disordered' 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.Pro1108Leu Uncertain significance ★★ ⚠ same residue
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

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-pro1108arg (accessed [today's date]).

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