Is MITF p.Asp246Val (c.737A>T) pathogenic?

MITF p.Asp246Val (c.737A>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.7749); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Asp246Val (c.737A>T)?

MITF p.Asp246Val (c.737A>T) is associated with hereditary neoplastic syndrome, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Asp246Val (c.737A>T) in the general population?

MITF p.Asp246Val (c.737A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Asp246Val (c.737A>T)?

AlphaMissense predicts likely pathogenic (score 0.7749) — an in-silico prediction, not a clinical call.

MITF p.Asp246Val

c.737A>T · VCV3758224

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7749 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7749	likely pathogenic
REVEL	0.493	indeterminate
SaProt	LLR -10.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	28.5	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.Asp246Val
Coding: c.737A>T
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69941306 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 246: the 'transactivation' 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

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

Similar variants

MITF p.Asp246Glu Uncertain significance ★★ ⚠ same residue
MITF p.Asp246Gly Uncertain significance ★★ ⚠ same residue
MITF p.Asp246= Likely benign ★★ same residue
MITF p.Asp246Asn Conflicting classifications of pathogenicity ★ same residue
MITF p.Asp246Tyr 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

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-asp246val (accessed [today's date]).

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