Is MITF p.Ser405Pro (c.1213T>C) pathogenic?

MITF p.Ser405Pro (c.1213T>C) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1198); Ultra-rare (popmax 0.0252%, nfe); Associated with Tietz syndrome.

What condition is associated with MITF p.Ser405Pro (c.1213T>C)?

MITF p.Ser405Pro (c.1213T>C) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Ser405Pro (c.1213T>C) in the general population?

MITF p.Ser405Pro (c.1213T>C) is ultra-rare (popmax 0.0252%, nfe) (gnomAD).

What do computational predictors say about MITF p.Ser405Pro (c.1213T>C)?

AlphaMissense predicts likely benign (score 0.1198) — an in-silico prediction, not a clinical call.

MITF p.Ser405Pro

c.1213T>C · rs104893747 · VCV14277

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.1198	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -3.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	21.5	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 0.0252% European (non-Finnish) · 297/1,180,032 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0185% 299/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0252%	3,973
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ser405Pro
Coding: c.1213T>C
MANE Select: NM_001354604
dbSNP: rs104893747
Type: single nucleotide variant
Location: chr3:69964880 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 405: a modified residue (phosphoserine; by gsk3); a UniProt-annotated variant site (in ws2a); the 'dna-binding regulation' region

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

Disease context

Tietz syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
MITF p.Arg310Gly 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-ser405pro (accessed [today's date]).

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