Is MKRN3 p.Ser41Cys (c.122C>G) pathogenic?

MKRN3 p.Ser41Cys (c.122C>G) is classified Uncertain significance in MKRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with MKRN3 p.Ser41Cys (c.122C>G)?

MKRN3 p.Ser41Cys (c.122C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MKRN3 p.Ser41Cys (c.122C>G) in the general population?

MKRN3 p.Ser41Cys (c.122C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MKRN3 p.Ser41Cys (c.122C>G)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

MKRN3 p.Ser41Cys

c.122C>G · rs749430619 · VCV2353500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.40	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 -0.29	GERP -1.8
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	14.7	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 0.00333% Admixed American · 2/60,018 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00186% 30/1,613,776 alleles · very rare exomes 29/1,461,610 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,009
European (non-Finnish)	0.0022%	45,383
South Asian	0.0022%	45,541

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.Ser41Cys
Coding: c.122C>G
MANE Select: NM_005664
dbSNP: rs749430619
Type: single nucleotide variant
Location: chr15:23565904 (GRCh38)
Gene constraint: LOEUF 1.665 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 64.59 · 1 PDB
Residue 41: 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-ser41cys (accessed [today's date]).

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