DPH1

Chr 17AR

diphthamide biosynthesis 1

Also known as: DEDSSH, DPH2L, DPH2L1, OVCA1

NCBI Gene: 1801 ENSG00000108963 UniProt: Q9BZG8 OMIM: 603527

DPH1 encodes an enzyme that catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine in elongation factor 2. Autosomal recessive mutations cause developmental delay with short stature, dysmorphic facial features, and sparse hair. The gene shows extremely high constraint against loss-of-function variants (pLI approaching 1), indicating that heterozygous loss is not tolerated in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 1.371 OMIM phenotype

Clinical Summary— DPH1

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Gene-Disease Validity (ClinGen)

developmental delay with short stature, dysmorphic facial features, and sparse hair · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 161 VUS of 230 total submissions

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GeneReview available — DPH1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.18Z-score

OE missense 1.03 (0.93–1.14)

278 obs / 269.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.98 (0.71–1.37)

0≤0.351.4

Missense OE?1.03 (0.93–1.14)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 25 / 25.4Missense obs/exp: 278 / 269.8Syn Z: -0.02

ClinVar Variant Classifications

230 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic9

VUS161

Likely Benign32

Benign8

Conflicting3

Pathogenic

Likely Pathogenic

161

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	0	0	6
Likely Pathogenic	6	3	0	0	9
VUS	2	155	4	0	161
Likely Benign	1	13	3	15	32
Benign	0	0	6	2	8
Conflicting	—				3
Total	13	173	13	17	219

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

View in ClinVar →

64 pathogenic / likely-pathogenic (of 76) ClinVar copy-number / structural variants overlap DPH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →