Is MKRN3 p.Pro486Arg (c.1457C>G) pathogenic?

MKRN3 p.Pro486Arg (c.1457C>G) is classified Benign/Likely benign in MKRN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.1325); Ultra-rare (popmax 0.0348%, nfe).

How common is MKRN3 p.Pro486Arg (c.1457C>G) in the general population?

MKRN3 p.Pro486Arg (c.1457C>G) is ultra-rare (popmax 0.0348%, nfe) (gnomAD).

What do computational predictors say about MKRN3 p.Pro486Arg (c.1457C>G)?

AlphaMissense predicts likely benign (score 0.1325) — an in-silico prediction, not a clinical call.

MKRN3 p.Pro486Arg

c.1457C>G · rs201786270 · VCV724914

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1325 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0348%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1325	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.99	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 -0.48	GERP -1.2
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	16.16	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

Grpmax group 0.0348% European (non-Finnish) · 411/1,180,034 alleles

Filtering AF 0.032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0309%

Overall 0.0621% 1,003/1,614,146 alleles · ultra-rare exomes 868/1,461,874 · genomes 135/152,272 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.847%	118
Remaining individualsnot grpmax-eligible	0.08%	1,250
European (non-Finnish)grpmax	0.0348%	2,871

Finnish 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.Pro486Arg
Coding: c.1457C>G
MANE Select: NM_005664
dbSNP: rs201786270
Type: single nucleotide variant
Location: chr15:23567239 (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

Similar variants

MKRN3 p.Pro486= Likely benign ★★ same residue
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
MKRN3 p.His119= 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-pro486arg (accessed [today's date]).

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