Is DUSP6 c.400+231T>C pathogenic?

DUSP6 c.400+231T>C is classified Benign in DUSP6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-12-24). Common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele.

DUSP6 c.400+231T>C

Q: How common is DUSP6 c.400+231T>C in the general population?

DUSP6 c.400+231T>C is common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs704079 · VCV1230616

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 13.4%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +231	deep intronic (+231 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1.5
Non-coding constraint	Z -0.32	1 kb window · o/e 1.02 · regional · uncalibrated
Overall
CADD	8.944	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.4% Admixed American · 4,278/31,878 alleles

Filtering AF 13.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 6.08% 42,384/697,522 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	20.3%	5
Admixed Americangrpmax	13.4%	7
European (non-Finnish)	6.38%	16
Remaining individualsnot grpmax-eligible	6.35%	16
Ashkenazi Jewishnot grpmax-eligible	6.33%	16
South Asian	5.64%	18
Finnishnot grpmax-eligible	5.08%	20
Middle Eastern	4.88%	21
African / African-American	2.97%	34
East Asian	1.67%	60

Amish 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
Coding: c.400+231T>C
MANE Select: NM_001946
dbSNP: rs704079
Type: single nucleotide variant
Location: chr12:89351409 (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.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.401-113T>A Benign ★★ same type
DUSP6 c.401-214G>A 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-c-400-plus-231t-c (accessed [today's date]).

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