Is DPH2 p.Arg477Ter (c.1429C>T) pathogenic?

DPH2 p.Arg477Ter (c.1429C>T) is classified Likely pathogenic in DPH2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-13). Very rare (popmax 0.00988%, sas); Associated with diphthamide-deficiency syndrome.

What condition is associated with DPH2 p.Arg477Ter (c.1429C>T)?

DPH2 p.Arg477Ter (c.1429C>T) is associated with diphthamide-deficiency syndrome, developmental delay with short stature, dysmorphic facial features, and sparse hair 2 (ClinVar).

How common is DPH2 p.Arg477Ter (c.1429C>T) in the general population?

DPH2 p.Arg477Ter (c.1429C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

DPH2 p.Arg477Ter

c.1429C>T · rs577890255 · VCV1687066

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Conditions

diphthamide-deficiency syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.5, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,084 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00304% 49/1,614,190 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,120
African / African-American	0.00666%	15,010
Admixed American	0.00333%	30,016
European (non-Finnish)	0.00271%	36,876
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: DPH2
Protein: p.Arg477Ter
Coding: c.1429C>T
MANE Select: NM_001384
dbSNP: rs577890255
Type: single nucleotide variant
Location: chr1:43972498 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.60
Residue 477: a UniProt-annotated variant site (in dedssh2; severely impairs diphthamide modification of elongation factor 2)

Full DPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

diphthamide-deficiency syndrome

Also linked: developmental delay with short stature, dysmorphic facial features, and sparse hair 2

Similar variants

DPH2 p.Arg477Gln Uncertain significance ★ ⚠ same residue
DPH2 p.Ser75Ter Likely pathogenic ★ same condition
DPH2 p.Arg201Cys Uncertain significance ★ same condition
DPH2 p.Gln308Ter Uncertain significance ★ same condition
DPH2 p.Arg282fs Conflicting classifications of pathogenicity ★ same condition
DPH2 p.Arg201His Uncertain significance ★★ ⚠ same type
DPH2 p.Ala310Val Uncertain significance ★ ⚠ same type
DPH2 p.Ala345Thr 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/dph2-p-arg477ter (accessed [today's date]).

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