Is MITF p.Ser258= (c.774G>A) pathogenic?

MITF p.Ser258= (c.774G>A) is classified Likely benign in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0201%, eas); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Ser258= (c.774G>A)?

MITF p.Ser258= (c.774G>A) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Ser258= (c.774G>A) in the general population?

MITF p.Ser258= (c.774G>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

MITF p.Ser258=

c.774G>A · rs1021664094 · VCV2935950

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -4.3
Overall
CADD	1.809	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,838 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00093% 15/1,612,946 alleles · ultra-rare exomes 13/1,461,056 · genomes 2/151,890 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,982
African / African-American	0.00267%	37,396
Admixed American	0.00167%	59,902
European (non-Finnish)	0.000254%	393,140

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.Ser258=
Coding: c.774G>A
MANE Select: NM_001354604
dbSNP: rs1021664094
Type: single nucleotide variant
Location: chr3:69949062 (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

Waardenburg syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome melanoma, cutaneous malignant, susceptibility to, 8 hereditary neoplastic syndrome

Similar variants

MITF p.Ser258Leu Uncertain significance ★★ ⚠ 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-ser258 (accessed [today's date]).

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