Is MITF p.Ser258Leu (c.773C>T) pathogenic?

MITF p.Ser258Leu (c.773C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.2981); Very rare (popmax 0.00223%, eas); Associated with Tietz syndrome.

What condition is associated with MITF p.Ser258Leu (c.773C>T)?

MITF p.Ser258Leu (c.773C>T) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Ser258Leu (c.773C>T) in the general population?

MITF p.Ser258Leu (c.773C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MITF p.Ser258Leu (c.773C>T)?

AlphaMissense predicts likely benign (score 0.2981) — an in-silico prediction, not a clinical call.

MITF p.Ser258Leu

c.773C>T · rs142900294 · VCV2096786

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.2981	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -8.99	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	28.3	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 0.00223% East Asian · 1/44,834 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,132 alleles · very rare exomes 4/1,460,984 · genomes 0/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,834
Admixed American	0.00167%	59,944
European (non-Finnish)	0.00017%	589,678

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.Ser258Leu
Coding: c.773C>T
MANE Select: NM_001354604
dbSNP: rs142900294
Type: single nucleotide variant
Location: chr3:69949061 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 258: the 'transactivation' 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 coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness hereditary neoplastic syndrome

Similar variants

MITF p.Ser258= Likely benign ★★ same residue
MITF p.Ser258fs Pathogenic ★ 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-ser258leu (accessed [today's date]).

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