Is MLN p.Val2Leu (c.4G>C) pathogenic?

MLN p.Val2Leu (c.4G>C) is classified Uncertain significance in MLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1926); Very rare (popmax 0.00221%, nfe).

How common is MLN p.Val2Leu (c.4G>C) in the general population?

MLN p.Val2Leu (c.4G>C) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about MLN p.Val2Leu (c.4G>C)?

AlphaMissense predicts likely benign (score 0.1926) — an in-silico prediction, not a clinical call.

MLN p.Val2Leu

c.4G>C · VCV4055582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1926	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.35	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 1.5	GERP 0.5, phastCons 1
Overall
CADD	17.18	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 0.00221% European (non-Finnish) · 26/1,178,644 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00167% 27/1,612,420 alleles · very rare exomes 25/1,460,166 · genomes 2/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00221%	45,333
African / African-American	0.00134%	74,898

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: MLN
Protein: p.Val2Leu
Coding: c.4G>C
MANE Select: NM_002418
Type: single nucleotide variant
Location: chr6:33801160 (GRCh38)
Structure: AlphaFold pLDDT 81.26

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

Similar variants

MLN p.Ala9Val Uncertain significance ★ ⚠ same type
MLN p.Arg43Trp Uncertain significance ★ ⚠ same type
MLN p.Gln47Arg Uncertain significance ★ ⚠ same type
MLN p.Glu75Gly Uncertain significance ★ ⚠ same type
MLN p.Gly103Arg Uncertain significance ★ ⚠ same type
MLN p.Ile69Asn Uncertain significance ★ ⚠ same type
MLN p.Leu11Gln Uncertain significance ★ same type
MLN p.Leu79Pro Uncertain significance ★ ⚠ 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/mln-p-val2leu (accessed [today's date]).

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