Is MITF p.Asn385Ser (c.1154A>G) pathogenic?

MITF p.Asn385Ser (c.1154A>G) is classified Conflicting classifications of pathogenicity in MITF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.5872); Very rare (popmax 0.00975%, nfe); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Asn385Ser (c.1154A>G)?

MITF p.Asn385Ser (c.1154A>G) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Asn385Ser (c.1154A>G) in the general population?

MITF p.Asn385Ser (c.1154A>G) is very rare (popmax 0.00975%, nfe) (gnomAD).

What do computational predictors say about MITF p.Asn385Ser (c.1154A>G)?

AlphaMissense predicts likely pathogenic (score 0.5872) — an in-silico prediction, not a clinical call.

MITF p.Asn385Ser

c.1154A>G · rs368915509 · VCV451477

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00975%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.5872	likely pathogenic
REVEL	0.269	benign-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	27.3	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 0.00975% European (non-Finnish) · 115/1,179,886 alleles

Filtering AF 0.00826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00774%

Overall 0.00756% 122/1,613,810 alleles · very rare exomes 111/1,461,630 · genomes 11/152,180 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00975%	10,260
Remaining individualsnot grpmax-eligible	0.0064%	15,618
Admixed American	0.00167%	59,988
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,072

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.Asn385Ser
Coding: c.1154A>G
MANE Select: NM_001354604
dbSNP: rs368915509
Type: single nucleotide variant
Location: chr3:69959395 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 385: a UniProt-annotated variant site (in ws2a); the 'leucine-zipper' region; 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

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

Similar variants

MITF p.Asn385Lys 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
MITF c.956-1G>A Pathogenic ★★ same condition
MITF p.Arg217Ter Pathogenic/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-asn385ser (accessed [today's date]).

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