Is MKRN3 p.Ala162fs (c.482dup) pathogenic?

MKRN3 p.Ala162fs (c.482dup) is classified Conflicting classifications of pathogenicity in MKRN3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.0164%, mid); Associated with MKRN3-related disorder.

What condition is associated with MKRN3 p.Ala162fs (c.482dup)?

MKRN3 p.Ala162fs (c.482dup) is associated with MKRN3-related disorder, precocious puberty, central, 2 (ClinVar).

How common is MKRN3 p.Ala162fs (c.482dup) in the general population?

MKRN3 p.Ala162fs (c.482dup) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

MKRN3 p.Ala162fs

c.482dup · rs763195944 · VCV56904

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

MKRN3-related disorder

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
Overall
CADD	26.7	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

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00409% 66/1,613,582 alleles · ultra-rare exomes 59/1,461,390 · genomes 7/152,192 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Finnishnot grpmax-eligible	0.0157%	6,355
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00446%	22,444
African / African-American	0.004%	24,981
European (non-Finnish)	0.00381%	26,223
South Asian	0.0011%	91,088

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.Ala162fs
Coding: c.482dup
MANE Select: NM_005664
dbSNP: rs763195944
Type: Duplication
Location: chr15:23566257 (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

MKRN3-related disorder

Also linked: precocious puberty, central, 2

Similar variants

MKRN3 p.Tyr418fs Uncertain significance ★ same condition
MKRN3 p.Tyr391Ter Pathogenic same condition
MKRN3 p.Ala288fs Pathogenic/Likely pathogenic ★★ same condition
MKRN3 c.-81C>T Uncertain significance ★★ same condition
MKRN3 p.Cys109Tyr Likely pathogenic ★ same condition
MKRN3 p.Pro161fs Pathogenic ★ 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-ala162fs (accessed [today's date]).

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