Is MITF p.Thr451= (c.1353G>A) pathogenic?

MITF p.Thr451= (c.1353G>A) is classified Conflicting classifications of pathogenicity in MITF (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00223%, eas); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Thr451= (c.1353G>A)?

MITF p.Thr451= (c.1353G>A) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Thr451= (c.1353G>A) in the general population?

MITF p.Thr451= (c.1353G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

MITF p.Thr451=

c.1353G>A · rs774944729 · VCV2180671

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -2.6	GERP -4.3
Overall
CADD	12.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,613,902 alleles · very rare exomes 24/1,461,866 · genomes 1/152,036 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
European (non-Finnish)	0.00186%	53,636
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Thr451=
Coding: c.1353G>A
MANE Select: NM_001354604
dbSNP: rs774944729
Type: single nucleotide variant
Location: chr3:69965020 (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

Waardenburg syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome melanoma, cutaneous malignant, susceptibility to, 8

Similar variants

MITF p.Thr451Lys Uncertain significance ★★ ⚠ same residue
MITF p.Thr451Met Uncertain significance ★★ ⚠ same residue
MITF p.Thr451Ala Uncertain significance ★ ⚠ same residue
MITF p.Thr451Arg 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-thr451 (accessed [today's date]).

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