Is MKRN3 p.Gly142Ala (c.425G>C) pathogenic?

MKRN3 p.Gly142Ala (c.425G>C) is classified Conflicting classifications of pathogenicity in MKRN3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-01). AlphaMissense: likely benign (0.087); Rare (popmax 0.221%, afr).

How common is MKRN3 p.Gly142Ala (c.425G>C) in the general population?

MKRN3 p.Gly142Ala (c.425G>C) is rare (popmax 0.221%, afr) (gnomAD).

What do computational predictors say about MKRN3 p.Gly142Ala (c.425G>C)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

MKRN3 p.Gly142Ala

c.425G>C · rs144864886 · VCV741460

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.221%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.58	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 3.2	GERP -2.5, phastCons 0.98
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	15.49	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 0.221% African / African-American · 166/75,076 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0237% 382/1,613,656 alleles · rare exomes 259/1,461,290 · genomes 123/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.221%	452
Admixed American	0.123%	811
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0448%	2,232
European (non-Finnish)	0.00915%	10,926
South Asian	0.0022%	45,538

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.Gly142Ala
Coding: c.425G>C
MANE Select: NM_005664
dbSNP: rs144864886
Type: single nucleotide variant
Location: chr15:23566207 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB
Residue 142: the 'disordered' region

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

Similar variants

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
MKRN3 p.Pro134= Benign/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-gly142ala (accessed [today's date]).

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