Is MITF p.Val503Met (c.1507G>A) pathogenic?

MITF p.Val503Met (c.1507G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-12). AlphaMissense: likely benign (0.1157); Ultra-rare (popmax 0.0117%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Val503Met (c.1507G>A)?

MITF p.Val503Met (c.1507G>A) is associated with hereditary neoplastic syndrome, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Val503Met (c.1507G>A) in the general population?

MITF p.Val503Met (c.1507G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about MITF p.Val503Met (c.1507G>A)?

AlphaMissense predicts likely benign (score 0.1157) — an in-silico prediction, not a clinical call.

MITF p.Val503Met

c.1507G>A · rs199578956 · VCV1196677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1157	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0117% Admixed American · 7/60,000 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00062% 10/1,613,818 alleles · ultra-rare exomes 9/1,461,662 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
African / African-American	0.00133%	74,918
European (non-Finnish)	0.00017%	589,939

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.Val503Met
Coding: c.1507G>A
MANE Select: NM_001354604
dbSNP: rs199578956
Type: single nucleotide variant
Location: chr3:69965174 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 503: the 'disordered' 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.Val503= Likely benign ★ 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-val503met (accessed [today's date]).

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