Is MITF p.Leu264Pro (c.791T>C) pathogenic?

MITF p.Leu264Pro (c.791T>C) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: ambiguous (0.5367); Absent from gnomAD v4.1; Associated with Tietz syndrome.

What condition is associated with MITF p.Leu264Pro (c.791T>C)?

MITF p.Leu264Pro (c.791T>C) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Leu264Pro (c.791T>C) in the general population?

MITF p.Leu264Pro (c.791T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Leu264Pro (c.791T>C)?

AlphaMissense predicts ambiguous (score 0.5367) — an in-silico prediction, not a clinical call.

MITF p.Leu264Pro

c.791T>C · rs2471620917 · VCV2103093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5367 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.5367	ambiguous
REVEL	0.216	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	25.3	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

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.Leu264Pro
Coding: c.791T>C
MANE Select: NM_001354604
dbSNP: rs2471620917
Type: single nucleotide variant
Location: chr3:69949079 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 264: the 'transactivation' region

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

Disease context

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

Also linked: Waardenburg syndrome type 2A melanoma, cutaneous malignant, susceptibility to, 8

Similar variants

MITF p.Leu264Val 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
MITF c.955+1G>A Likely pathogenic ★★ same condition
MITF c.956-1G>A Pathogenic ★★ same condition
MITF p.Arg217Ter Pathogenic/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-leu264pro (accessed [today's date]).

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