Is MKRN3 p.Arg345His (c.1034G>A) pathogenic?

MKRN3 p.Arg345His (c.1034G>A) is classified Uncertain significance in MKRN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-29). AlphaMissense: likely pathogenic (0.7948); Very rare (popmax 0.00267%, afr).

How common is MKRN3 p.Arg345His (c.1034G>A) in the general population?

MKRN3 p.Arg345His (c.1034G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MKRN3 p.Arg345His (c.1034G>A)?

AlphaMissense predicts likely pathogenic (score 0.7948) — an in-silico prediction, not a clinical call.

MKRN3 p.Arg345His

c.1034G>A · rs375705600 · VCV1677218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7948	likely pathogenic
REVEL	0.708	pathogenic-leaning
SaProt	LLR -12.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,928 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,614,106 alleles · very rare exomes 16/1,461,894 · genomes 4/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,464
European (non-Finnish)	0.00153%	65,559

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.Arg345His
Coding: c.1034G>A
MANE Select: NM_005664
dbSNP: rs375705600
Type: single nucleotide variant
Location: chr15:23566816 (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 c.-81C>T 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
MKRN3 p.Pro221= 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-arg345his (accessed [today's date]).

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