Is MITF p.Pro415Leu (c.1244C>T) pathogenic?

MITF p.Pro415Leu (c.1244C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-15). AlphaMissense: likely benign (0.1275); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Pro415Leu (c.1244C>T)?

MITF p.Pro415Leu (c.1244C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MITF p.Pro415Leu (c.1244C>T) in the general population?

MITF p.Pro415Leu (c.1244C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MITF p.Pro415Leu (c.1244C>T)?

AlphaMissense predicts likely benign (score 0.1275) — an in-silico prediction, not a clinical call.

MITF p.Pro415Leu

c.1244C>T · rs2107551959 · VCV1326018

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1275	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.66 · evaluated, not missing
Pangolin	Δ0.21	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	25.0	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 0.00133% African / African-American · 1/75,026 alleles

Overall 6.2e-05% 1/1,614,136 alleles · very rare exomes 1/1,461,874 · genomes 0/152,262 · joint denominator

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: MITF
Protein: p.Pro415Leu
Coding: c.1244C>T
MANE Select: NM_001354604
dbSNP: rs2107551959
Type: single nucleotide variant
Location: chr3:69964911 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 415: the 'dna-binding regulation' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MITF p.Pro415Ser Uncertain significance ★★ ⚠ same residue
MITF p.Pro415= Likely benign ★ same residue
MITF p.Arg362Ter Pathogenic/Likely pathogenic ★★ same condition
MITF c.881-9C>G Uncertain significance ★★ same condition
MITF p.Ala148Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala152Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala177Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala183Ser 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/mitf-p-pro415leu (accessed [today's date]).

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