Is MITF p.Leu334Pro (c.1001T>C) pathogenic?

MITF p.Leu334Pro (c.1001T>C) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-22). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Leu334Pro (c.1001T>C)?

MITF p.Leu334Pro (c.1001T>C) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Leu334Pro (c.1001T>C) in the general population?

MITF p.Leu334Pro (c.1001T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Leu334Pro (c.1001T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

MITF p.Leu334Pro

c.1001T>C · rs2471644672 · VCV2949784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 4% in MITF
REVEL	0.977	strongly pathogenic-leaning
SaProt	LLR -15.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.38	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 7,490 bp · p 4.1e-07 · regional, not allelic
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MITF
Protein: p.Leu334Pro
Coding: c.1001T>C
MANE Select: NM_001354604
dbSNP: rs2471644672
Type: single nucleotide variant
Location: chr3:69956500 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 334: the bhlh domain; an α-helix

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome Waardenburg syndrome type 2A coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

For MITF-related melanoma and renal cell carcinoma predisposition syndrome (Orphanet):

Onset: Adult, Elderly

Similar variants

MITF p.Leu334Arg Likely pathogenic ★ same residue
MITF p.Leu334= Likely benign ★ same residue
MITF p.Leu334fs Pathogenic ★ same residue
MITF p.Leu334Val Uncertain significance ★ ⚠ same residue
MITF c.1031+1G>A Pathogenic ★★ same condition
MITF c.1179+1G>A Pathogenic ★★ same condition
MITF c.355-1062G>C Pathogenic/Likely pathogenic ★★ same condition
MITF c.880+1G>A Likely pathogenic ★★ 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-leu334pro (accessed [today's date]).

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