Is DUSP6 p.Ser182Phe (c.545C>T) pathogenic?

DUSP6 p.Ser182Phe (c.545C>T) is classified Conflicting classifications of pathogenicity in DUSP6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-25). AlphaMissense: ambiguous (0.556); Rare (popmax 0.119%, nfe); Associated with hypogonadotropic hypogonadism 19 with or without anosmia.

What condition is associated with DUSP6 p.Ser182Phe (c.545C>T)?

DUSP6 p.Ser182Phe (c.545C>T) is associated with hypogonadotropic hypogonadism 19 with or without anosmia (ClinVar).

How common is DUSP6 p.Ser182Phe (c.545C>T) in the general population?

DUSP6 p.Ser182Phe (c.545C>T) is rare (popmax 0.119%, nfe) (gnomAD).

What do computational predictors say about DUSP6 p.Ser182Phe (c.545C>T)?

AlphaMissense predicts ambiguous (score 0.556) — an in-silico prediction, not a clinical call.

DUSP6 p.Ser182Phe

c.545C>T · rs139318648 · VCV50855

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.556 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.119%, nfe)

Conditions

hypogonadotropic hypogonadism 19 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.556	ambiguous
REVEL	0.376	indeterminate
SaProt	LLR -9.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,392 bp · p 0.98 · regional, not allelic
Overall
CADD	29.2	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 0.119% European (non-Finnish) · 1,400/1,179,964 alleles

Filtering AF 0.113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.0933% 1,506/1,613,908 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.43%	70
European (non-Finnish)grpmax	0.119%	843
Remaining individualsnot grpmax-eligible	0.0576%	1,735
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Finnishnot grpmax-eligible	0.0266%	3,762
Middle Eastern	0.0164%	6,084
African / African-American	0.0147%	6,812
South Asian	0.0121%	8,281
Admixed American	0.00333%	30,007

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
Protein: p.Ser182Phe
Coding: c.545C>T
MANE Select: NM_001946
dbSNP: rs139318648
Type: single nucleotide variant
Location: chr12:89350881 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 2 PDB
Residue 182: a UniProt-annotated variant site (in hh19; the patient carries a second mutation in the hh-associated gene fgfr1); the 'disordered' region

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.Val114Leu Benign ★★ same condition
DUSP6 p.Cys39Ter Pathogenic ★ same condition
DUSP6 p.Asn189Ser 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-ser182phe (accessed [today's date]).

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