Is MKRN3 p.Arg365Ser (c.1095G>T) pathogenic?

MKRN3 p.Arg365Ser (c.1095G>T) is classified Pathogenic in MKRN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-06-27). AlphaMissense: likely pathogenic (0.9935); Absent from gnomAD v4.1; Associated with precocious puberty, central, 2.

What condition is associated with MKRN3 p.Arg365Ser (c.1095G>T)?

MKRN3 p.Arg365Ser (c.1095G>T) is associated with precocious puberty, central, 2 (ClinVar).

How common is MKRN3 p.Arg365Ser (c.1095G>T) in the general population?

MKRN3 p.Arg365Ser (c.1095G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MKRN3 p.Arg365Ser (c.1095G>T)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

MKRN3 p.Arg365Ser

c.1095G>T · rs879255240 · VCV56903

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

precocious puberty, central, 2

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic ✓ concordant with ClinVar · top 2% in MKRN3
REVEL	0.617	indeterminate
SaProt	LLR -14.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.89, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	24.4	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

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.Arg365Ser
Coding: c.1095G>T
MANE Select: NM_005664
dbSNP: rs879255240
Type: single nucleotide variant
Location: chr15:23566877 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB
Residue 365: a UniProt-annotated variant site (in cppb2)

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 c.-81C>T Uncertain significance ★★ same condition
MKRN3 p.Cys109Tyr Likely pathogenic ★ same condition
MKRN3 p.Cys35Gly Uncertain significance ★ ⚠ same condition
MKRN3 p.Ile100Met Uncertain significance ★ ⚠ same condition
MKRN3 p.Pro161Leu Uncertain significance ★ ⚠ same condition
MKRN3 p.Arg328Cys Pathogenic same condition
MKRN3 p.Pro161fs Pathogenic ★ same condition
MKRN3 p.Ala162fs Conflicting classifications of pathogenicity ★ 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-arg365ser (accessed [today's date]).

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