Is MITF p.Pro492Ser (c.1474C>T) pathogenic?

MITF p.Pro492Ser (c.1474C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.1909); Very rare (popmax 0.00801%, afr); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Pro492Ser (c.1474C>T)?

MITF p.Pro492Ser (c.1474C>T) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Pro492Ser (c.1474C>T) in the general population?

MITF p.Pro492Ser (c.1474C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about MITF p.Pro492Ser (c.1474C>T)?

AlphaMissense predicts likely benign (score 0.1909) — an in-silico prediction, not a clinical call.

MITF p.Pro492Ser

c.1474C>T · rs781298935 · VCV1313766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1909	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	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 0.00801% African / African-American · 6/74,922 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00527% 85/1,613,976 alleles · very rare exomes 83/1,461,848 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
European (non-Finnish)	0.00661%	15,128
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Pro492Ser
Coding: c.1474C>T
MANE Select: NM_001354604
dbSNP: rs781298935
Type: single nucleotide variant
Location: chr3:69965141 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB

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

Similar variants

MITF p.Pro492= Likely benign ★★ same residue
MITF p.Pro492Ala Uncertain significance ★ ⚠ same residue
MITF p.Pro492Leu 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

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-pro492ser (accessed [today's date]).

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