Is MITF p.Met169Val (c.505A>G) pathogenic?

MITF p.Met169Val (c.505A>G) is classified Conflicting classifications of pathogenicity in MITF (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.00267%, afr); Associated with MITF-related disorder.

What condition is associated with MITF p.Met169Val (c.505A>G)?

MITF p.Met169Val (c.505A>G) is associated with MITF-related disorder, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Met169Val (c.505A>G) in the general population?

MITF p.Met169Val (c.505A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MITF p.Met169Val (c.505A>G)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

MITF p.Met169Val

c.505A>G · rs143224466 · VCV346494

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MITF-related disorder

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -5.26	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 5.3	GERP 0.95, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	22.5	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 0.00267% African / African-American · 2/74,934 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000558% 9/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,467
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000508%	196,670

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.Met169Val
Coding: c.505A>G
MANE Select: NM_001354604
dbSNP: rs143224466
Type: single nucleotide variant
Location: chr3:69937972 (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

MITF-related disorder

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

Similar variants

MITF p.Met169Leu Uncertain significance ★★ ⚠ same residue
MITF p.Met169Thr 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

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-met169val (accessed [today's date]).

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