Is MKRN3 p.Ser46Ter (c.137C>A) pathogenic?

MKRN3 p.Ser46Ter (c.137C>A) is classified Likely pathogenic in MKRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-02). Absent from gnomAD v4.1; Associated with Prader-Willi syndrome.

What condition is associated with MKRN3 p.Ser46Ter (c.137C>A)?

MKRN3 p.Ser46Ter (c.137C>A) is associated with Prader-Willi syndrome (ClinVar).

How common is MKRN3 p.Ser46Ter (c.137C>A) in the general population?

MKRN3 p.Ser46Ter (c.137C>A) is absent from gnomAD v4.1 (gnomAD).

How is Prader-Willi syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

MKRN3 p.Ser46Ter

c.137C>A · VCV3779852

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Prader-Willi syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP 0.36
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MKRN3
Protein: p.Ser46Ter
Coding: c.137C>A
MANE Select: NM_005664
Type: single nucleotide variant
Location: chr15:23565919 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB
Residue 46: the 'disordered' region

Full MKRN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Prader-Willi syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Prader-Willi syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MKRN3 p.Ile100Met Uncertain significance ★ ⚠ same condition
MKRN3 p.Pro161Leu Uncertain significance ★ ⚠ same condition
MKRN3 c.-81C>T Uncertain significance ★★ same type
MKRN3 p.Arg345His Uncertain significance ★★ ⚠ same type
MKRN3 p.Gly172Asp Uncertain significance ★★ ⚠ same type
MKRN3 p.His496Arg Uncertain significance ★★ ⚠ same type
MKRN3 p.Thr145Met Uncertain significance ★★ ⚠ same type
MKRN3 p.Gly131= Benign/Likely benign ★★ same type

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/mkrn3-p-ser46ter (accessed [today's date]).

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