Is DUSP6 p.Phe77Ile (c.229T>A) pathogenic?

DUSP6 p.Phe77Ile (c.229T>A) is classified Uncertain significance in DUSP6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-02). AlphaMissense: likely benign (0.1752); Ultra-rare (popmax 0.0165%, mid); Associated with hypogonadotropic hypogonadism 19 with or without anosmia.

What condition is associated with DUSP6 p.Phe77Ile (c.229T>A)?

DUSP6 p.Phe77Ile (c.229T>A) is associated with hypogonadotropic hypogonadism 19 with or without anosmia (ClinVar).

How common is DUSP6 p.Phe77Ile (c.229T>A) in the general population?

DUSP6 p.Phe77Ile (c.229T>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DUSP6 p.Phe77Ile (c.229T>A)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

DUSP6 p.Phe77Ile

c.229T>A · rs587776978 · VCV50857

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 19 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.68	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 11	GERP -0.38, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,392 bp · p 0.98 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000823% 12/1,458,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.00481%	20,798
European (non-Finnish)	0.000678%	147,418

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.Phe77Ile
Coding: c.229T>A
MANE Select: NM_001946
dbSNP: rs587776978
Type: single nucleotide variant
Location: chr12:89351811 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 2 PDB
Residue 77: the rhodanese domain; a UniProt-annotated variant site (in hh19)

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.Val114Leu Benign ★★ 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-phe77ile (accessed [today's date]).

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