Is MITF p.Arg370Cys (c.1108C>T) pathogenic?

MITF p.Arg370Cys (c.1108C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-20). AlphaMissense: ambiguous (0.4023); Very rare (popmax 0.00161%, nfe); Associated with Tietz syndrome.

What condition is associated with MITF p.Arg370Cys (c.1108C>T)?

MITF p.Arg370Cys (c.1108C>T) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Arg370Cys (c.1108C>T) in the general population?

MITF p.Arg370Cys (c.1108C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about MITF p.Arg370Cys (c.1108C>T)?

AlphaMissense predicts ambiguous (score 0.4023) — an in-silico prediction, not a clinical call.

MITF p.Arg370Cys

c.1108C>T · rs372113245 · VCV2939722

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.4023	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -13.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.00161% European (non-Finnish) · 19/1,179,952 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,613,972 alleles · very rare exomes 20/1,461,736 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,103
South Asian	0.0011%	91,082

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.Arg370Cys
Coding: c.1108C>T
MANE Select: NM_001354604
dbSNP: rs372113245
Type: single nucleotide variant
Location: chr3:69959349 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 370: an α-helix

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 p.Arg370Gly Uncertain significance ★★ ⚠ same residue
MITF p.Arg370= Likely benign ★★ same residue
MITF p.Arg370His 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-arg370cys (accessed [today's date]).

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