Is MITF p.Ser357Pro (c.1069T>C) pathogenic?

MITF p.Ser357Pro (c.1069T>C) is classified Pathogenic in MITF (ClinVar, No assertion criteria, 1 submitter; last evaluated 1995-11-01). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Ser357Pro (c.1069T>C)?

MITF p.Ser357Pro (c.1069T>C) is associated with Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Ser357Pro (c.1069T>C) in the general population?

MITF p.Ser357Pro (c.1069T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Ser357Pro (c.1069T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

MITF p.Ser357Pro

c.1069T>C · rs104893744 · VCV14273

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 4% in MITF
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -15.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 7,490 bp · p 4.1e-07 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MITF
Protein: p.Ser357Pro
Coding: c.1069T>C
MANE Select: NM_001354604
dbSNP: rs104893744
Type: single nucleotide variant
Location: chr3:69959310 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 357: the bhlh domain; a UniProt-annotated variant site (in ws2a); an α-helix

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

Similar variants

MITF p.Ser357= Likely benign ★★ same residue
MITF p.Ser357Tyr Likely 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-ser357pro (accessed [today's date]).

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