Is MKRN3 p.Pro161fs (c.482del) pathogenic?

MKRN3 p.Pro161fs (c.482del) is classified Pathogenic in MKRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-09). Very rare (popmax 0.00133%, afr); Associated with precocious puberty, central, 2.

What condition is associated with MKRN3 p.Pro161fs (c.482del)?

MKRN3 p.Pro161fs (c.482del) is associated with precocious puberty, central, 2 (ClinVar).

How common is MKRN3 p.Pro161fs (c.482del) in the general population?

MKRN3 p.Pro161fs (c.482del) is very rare (popmax 0.00133%, afr) (gnomAD).

MKRN3 p.Pro161fs

c.482del · rs763195944 · VCV2431610

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

precocious puberty, central, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	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 · substitutions only
Constraint at this position
Conservation	phyloP 3.7	GERP -2.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,064 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,613,750 alleles · very rare exomes 5/1,461,440 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-Americangrpmax	0.00133%	75,064
European (non-Finnish)	0.000254%	393,342

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MKRN3
Protein: p.Pro161fs
Coding: c.482del
MANE Select: NM_005664
dbSNP: rs763195944
Type: Deletion
Location: chr15:23566258 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB

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

Disease context

precocious puberty, central, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MKRN3 p.Pro161Leu Uncertain significance ★ ⚠ same residue
MKRN3 p.Pro161Ser Uncertain significance ★ ⚠ same residue
MKRN3 p.Arg213fs Pathogenic same condition
MKRN3 c.-81C>T Uncertain significance ★★ same condition
MKRN3 p.Cys109Tyr Likely pathogenic ★ same condition
MKRN3 p.Ala162fs Conflicting classifications of pathogenicity ★ same condition
MKRN3 p.Cys35Gly Uncertain significance ★ ⚠ same condition
MKRN3 p.Ile100Met 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/mkrn3-p-pro161fs (accessed [today's date]).

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