DPH2

Chr 1AR

diphthamide biosynthesis 2

Also known as: DEDSSH2, DPH2L2

NCBI Gene: 1802 ENSG00000132768 OMIM: 603456

The DPH2 protein is required for diphthamide biosynthesis, a post-translational modification of histidine in elongation factor 2, where it facilitates reduction of the iron-sulfur cluster in the DPH1 subunit. Mutations cause autosomal recessive developmental delay with short stature, dysmorphic facial features, and sparse hair. The gene shows low constraint against loss-of-function variants (pLI 0.00001), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain, and thus probably functions in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue present in elongation factor 2 (EF2) that is the target of diphtheria toxin ADP-ribosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.951 OMIM phenotype

Clinical Summary— DPH2

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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

2 unique Pathogenic / Likely Pathogenic· 79 VUS of 99 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.000

Z-score 1.73

OE 0.57 (0.36–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.76Z-score

OE missense 0.88 (0.79–0.97)

261 obs / 297.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.36–0.95)

0≤0.351.4

Missense OE?0.88 (0.79–0.97)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 11 / 19.2Missense obs/exp: 261 / 297.9Syn Z: 0.22

ClinVar Variant Classifications

99 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS79

Likely Benign7

Conflicting3

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	0	0	0	2
VUS	1	78	0	0	79
Likely Benign	0	4	0	3	7
Benign	0	0	0	0	0
Conflicting	—				3
Total	3	82	0	3	91

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap DPH2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →