Is MKRN3 p.Pro86Leu (c.257C>T) pathogenic?

MKRN3 p.Pro86Leu (c.257C>T) is classified Uncertain significance in MKRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-21). AlphaMissense: likely benign (0.091); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with MKRN3 p.Pro86Leu (c.257C>T)?

MKRN3 p.Pro86Leu (c.257C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MKRN3 p.Pro86Leu (c.257C>T) in the general population?

MKRN3 p.Pro86Leu (c.257C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MKRN3 p.Pro86Leu (c.257C>T)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

MKRN3 p.Pro86Leu

c.257C>T · rs960074606 · VCV2339100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.86	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 -1.1	GERP -2.8
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	2.636	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,034 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000558% 9/1,614,010 alleles · very rare exomes 9/1,461,672 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,011
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.000339%	295,010

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.Pro86Leu
Coding: c.257C>T
MANE Select: NM_005664
dbSNP: rs960074606
Type: single nucleotide variant
Location: chr15:23566039 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB
Residue 86: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MKRN3 p.Gly172Asp Uncertain significance ★★ ⚠ same condition
MKRN3 p.His496Arg Uncertain significance ★★ ⚠ same condition
MKRN3 p.Thr145Met Uncertain significance ★★ ⚠ same condition
MKRN3 p.Ala127Val Uncertain significance ★ ⚠ same condition
MKRN3 p.Ala137Asp Uncertain significance ★ ⚠ same condition
MKRN3 p.Ala137Val Uncertain significance ★ ⚠ same condition
MKRN3 p.Ala440Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
MKRN3 p.Ala51Gly 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-pro86leu (accessed [today's date]).

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