Is MKRN3 p.Ser349Ile (c.1046G>T) pathogenic?

MKRN3 p.Ser349Ile (c.1046G>T) is classified Uncertain significance in MKRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-12-15). AlphaMissense: ambiguous (0.5583); Ultra-rare (popmax 0.0147%, afr).

How common is MKRN3 p.Ser349Ile (c.1046G>T) in the general population?

MKRN3 p.Ser349Ile (c.1046G>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about MKRN3 p.Ser349Ile (c.1046G>T)?

AlphaMissense predicts ambiguous (score 0.5583) — an in-silico prediction, not a clinical call.

MKRN3 p.Ser349Ile

c.1046G>T · rs771912869 · VCV381799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5583	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,520 bp · p 0.0015 · regional, not allelic
Overall
CADD	16.78	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 0.0147% African / African-American · 11/74,924 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00112% 18/1,614,080 alleles · ultra-rare exomes 9/1,461,894 · genomes 9/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,811
South Asian	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ser349Ile
Coding: c.1046G>T
MANE Select: NM_005664
dbSNP: rs771912869
Type: single nucleotide variant
Location: chr15:23566828 (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.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-ser349ile (accessed [today's date]).

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