Is MITF p.Ser501Phe (c.1502C>T) pathogenic?

MITF p.Ser501Phe (c.1502C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-21). AlphaMissense: likely pathogenic (0.6884); Ultra-rare (popmax 0.0133%, amr); Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Ser501Phe (c.1502C>T)?

MITF p.Ser501Phe (c.1502C>T) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Ser501Phe (c.1502C>T) in the general population?

MITF p.Ser501Phe (c.1502C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about MITF p.Ser501Phe (c.1502C>T)?

AlphaMissense predicts likely pathogenic (score 0.6884) — an in-silico prediction, not a clinical call.

MITF p.Ser501Phe

c.1502C>T · rs1465717485 · VCV2077794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

Computational evidence

Protein change
AlphaMissense	0.6884	likely pathogenic
REVEL	0.468	indeterminate
SaProt	LLR -7.30	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	26.5	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 0.0133% Admixed American · 8/59,992 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000558% 9/1,613,814 alleles · ultra-rare exomes 4/1,461,688 · genomes 5/152,126 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Ser501Phe
Coding: c.1502C>T
MANE Select: NM_001354604
dbSNP: rs1465717485
Type: single nucleotide variant
Location: chr3:69965169 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 501: the 'disordered' region

Full MITF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma, cutaneous malignant, susceptibility to, 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome Waardenburg syndrome type 2A

For MITF-related melanoma and renal cell carcinoma predisposition syndrome (Orphanet):

Onset: Adult, Elderly

Similar variants

MITF p.Ser501Thr 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
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-ser501phe (accessed [today's date]).

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