Is MITF p.Leu448Pro (c.1343T>C) pathogenic?

MITF p.Leu448Pro (c.1343T>C) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-09). AlphaMissense: likely pathogenic (0.799); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Leu448Pro (c.1343T>C)?

MITF p.Leu448Pro (c.1343T>C) is associated with hereditary neoplastic syndrome, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Leu448Pro (c.1343T>C) in the general population?

MITF p.Leu448Pro (c.1343T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MITF p.Leu448Pro (c.1343T>C)?

AlphaMissense predicts likely pathogenic (score 0.799) — an in-silico prediction, not a clinical call.

MITF p.Leu448Pro

c.1343T>C · VCV3396332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.799	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	22.0	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 0.000339% European (non-Finnish) · 4/1,180,008 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,894 alleles · very rare exomes 3/1,461,882 · genomes 1/152,012 · 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.Leu448Pro
Coding: c.1343T>C
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69965010 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB

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

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

Similar variants

MITF p.Leu448= Likely benign ★★ same residue
MITF p.Leu448Arg Uncertain significance ★ ⚠ same residue
MITF p.Leu448Val 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

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-leu448pro (accessed [today's date]).

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