Is DUSP6 p.Thr365Ile (c.1094C>T) pathogenic?

DUSP6 p.Thr365Ile (c.1094C>T) is classified Uncertain significance in DUSP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.543); Very rare (popmax 0.00223%, eas).

How common is DUSP6 p.Thr365Ile (c.1094C>T) in the general population?

DUSP6 p.Thr365Ile (c.1094C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DUSP6 p.Thr365Ile (c.1094C>T)?

AlphaMissense predicts ambiguous (score 0.543) — an in-silico prediction, not a clinical call.

DUSP6 p.Thr365Ile

c.1094C>T · VCV4015454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.543	ambiguous
REVEL	0.199	benign-leaning
SaProt	LLR -7.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.45, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 1,389 bp · p 0.00012 · regional, not allelic
Overall
CADD	24.8	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 0.00223% East Asian · 1/44,894 alleles

Overall 0.00062% 10/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,942
East Asiangrpmax	0.00223%	44,894

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DUSP6
Protein: p.Thr365Ile
Coding: c.1094C>T
MANE Select: NM_001946
Type: single nucleotide variant
Location: chr12:89349306 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 2 PDB

Full DUSP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DUSP6 p.Thr365= Likely benign ★ same residue
DUSP6 p.Ala141Asp Uncertain significance ★★ ⚠ same type
DUSP6 p.Ala57Thr Uncertain significance ★★ ⚠ same type
DUSP6 p.Asp93Glu Uncertain significance ★★ ⚠ same type
DUSP6 p.Glu32Lys Uncertain significance ★★ ⚠ same type
DUSP6 p.Gly30Cys Uncertain significance ★★ ⚠ same type
DUSP6 p.Phe77Ile Uncertain significance ★★ ⚠ same type
DUSP6 c.400+231T>C Benign ★★ same type

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/dusp6-p-thr365ile (accessed [today's date]).

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