DPH1

Chr 17AR

diphthamide biosynthesis 1

Also known as: DEDSSH, DPH2L, DPH2L1, OVCA1

NCBI Gene: 1801ENSG00000108963UniProt: Q9BZG8

The protein encoded by this gene is an enzyme involved in the biosynthesis of diphthamide, a modified histidine found only in elongation factor-2 (EEF2). Diphthamide residues in EEF2 are targeted for ADP-ribosylation by diphtheria toxin and Pseudomonas exotoxin A. Defects in this gene have been associated with both ovarian cancer and autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. [provided by RefSeq, Oct 2016]

Primary Disease Associations & Inheritance

Developmental delay with short stature, dysmorphic facial features, and sparse hairMIM #616901
AR
292
ClinVar variants
77
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— DPH1
🧬
Gene-Disease Validity (ClinGen)
developmental delay with short stature, dysmorphic facial features, and sparse hair · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
77 Pathogenic / Likely Pathogenic· 172 VUS of 292 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.37LOEUF
pLI 0.000
Z-score 0.08
OE 0.98 (0.71–1.37)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.18Z-score
OE missense 1.03 (0.93–1.14)
278 obs / 269.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.98 (0.71–1.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.93–1.14)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 25 / 25.4Missense obs/exp: 278 / 269.8Syn Z: -0.02

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63
Likely Pathogenic14
VUS172
Likely Benign32
Benign8
Conflicting3
63
Pathogenic
14
Likely Pathogenic
172
VUS
32
Likely Benign
8
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
2
59
0
63
Likely Pathogenic
4
3
7
0
14
VUS
2
152
18
0
172
Likely Benign
1
13
3
15
32
Benign
0
0
6
2
8
Conflicting
—3
Total91709317292

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DPH1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental delay with short stature, dysmorphic facial features, and sparse hair

MIM #616901

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — DPH1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
Alazami AM et al.·Cell Rep
2015
DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models.
Ütkür K et al.·Dis Model Mech
2023Functional
Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities.
Nakajima J et al.·J Hum Genet
2018Review
DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients.
Urreizti R et al.·Eur J Hum Genet
2020Case report
Influence of DPH1 and DPH5 Protein Variants on the Synthesis of Diphthamide, the Target of ADPRibosylating Toxins.
Mayer K et al.·Toxins (Basel)
2017
Diphthamide - a conserved modification of eEF2 with clinical relevance.
Schaffrath R et al.·Trends Mol Med
2024Review
Expanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency.
Politano D et al.·Genes (Basel)
2025
Assessment of Rare Genetic Variants to Identify Candidate Modifier Genes Underlying Neurological Manifestations in Neurofibromatosis 1 Patients.
Tang J et al.·Genes (Basel)
2022Review
Recessive loss-of-function variants in DPH1 identified as the molecular cause in a sibling pair previously diagnosed with Fine-Lubinsky syndrome.
Waskow ER et al.·Am J Med Genet A
2025Case report
A novel homozygous DPH1 mutation causes intellectual disability and unique craniofacial features.
Sekiguchi F et al.·J Hum Genet
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools