Is MITF p.Arg321Ter (c.961C>T) pathogenic?

MITF p.Arg321Ter (c.961C>T) is classified Pathogenic in MITF (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-07). Very rare (popmax 8.48e-05%, nfe); Associated with MITF-related disorder.

What condition is associated with MITF p.Arg321Ter (c.961C>T)?

MITF p.Arg321Ter (c.961C>T) is associated with MITF-related disorder, hearing loss disorder, ear malformation (ClinVar).

How common is MITF p.Arg321Ter (c.961C>T) in the general population?

MITF p.Arg321Ter (c.961C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

MITF p.Arg321Ter

c.961C>T · rs104893746 · VCV14276

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

MITF-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 10
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -2, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,038 alleles

Overall 6.2e-05% 1/1,612,836 alleles · very rare exomes 1/1,460,658 · genomes 0/152,178 · joint denominator

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.Arg321Ter
Coding: c.961C>T
MANE Select: NM_001354604
dbSNP: rs104893746
Type: single nucleotide variant
Location: chr3:69956460 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 321: the bhlh domain

Full MITF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MITF-related disorder

Also linked: hearing loss disorder ear malformation heterochromia iridis Waardenburg syndrome type 2A

Similar variants

MITF p.Arg321Gly Likely pathogenic ★ same residue
MITF p.Arg321Leu Likely pathogenic ★ same residue
MITF p.Arg321Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MITF p.Arg321= Likely benign ★ 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

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-arg321ter (accessed [today's date]).

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