Is DUSP6 p.Val114Leu (c.340G>T) pathogenic?

DUSP6 p.Val114Leu (c.340G>T) is classified Benign in DUSP6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2946); Common (popmax 57.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hypogonadotropic hypogonadism 19 with or without anosmia.

What condition is associated with DUSP6 p.Val114Leu (c.340G>T)?

DUSP6 p.Val114Leu (c.340G>T) is associated with hypogonadotropic hypogonadism 19 with or without anosmia (ClinVar).

What do computational predictors say about DUSP6 p.Val114Leu (c.340G>T)?

AlphaMissense predicts likely benign (score 0.2946) — an in-silico prediction, not a clinical call.

DUSP6 p.Val114Leu

Q: How common is DUSP6 p.Val114Leu (c.340G>T) in the general population?

DUSP6 p.Val114Leu (c.340G>T) is common (popmax 57.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.340G>T · rs2279574 · VCV802882

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2946 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57.3%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 19 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.2946	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,392 bp · p 0.98 · regional, not allelic
Overall
CADD	23.4	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 57.3% East Asian · 25,344/44,248 alleles

Filtering AF 56.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.4%

Overall 52.6% 843,949/1,603,502 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	62.8%	2
East Asiangrpmax	57.3%	2
Amishnot grpmax-eligible	55.5%	2
European (non-Finnish)	54%	2
Remaining individualsnot grpmax-eligible	51.6%	2
Admixed American	50.6%	2
Middle Eastern	49.4%	2
Ashkenazi Jewishnot grpmax-eligible	49.2%	2
South Asian	48.1%	2
African / African-American	29.1%	3

Finnish 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.Val114Leu
Coding: c.340G>T
MANE Select: NM_001946
dbSNP: rs2279574
Type: single nucleotide variant
Location: chr12:89351700 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 2 PDB
Residue 114: the rhodanese domain; an α-helix; a UniProt-annotated variant site (in)

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

Disease context

hypogonadotropic hypogonadism 19 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DUSP6 p.Ala57Thr Uncertain significance ★★ ⚠ same condition
DUSP6 p.Phe77Ile Uncertain significance ★★ ⚠ same condition
DUSP6 p.Cys39Ter Pathogenic ★ same condition
DUSP6 p.Asn189Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
DUSP6 p.Ser182Phe Conflicting classifications of pathogenicity ★ ⚠ same condition
DUSP6 p.Ala141Asp Uncertain significance ★★ ⚠ same type
DUSP6 p.Asp93Glu Uncertain significance ★★ ⚠ same type
DUSP6 p.Glu32Lys Uncertain significance ★★ ⚠ 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-val114leu (accessed [today's date]).

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