Is DPH5 p.His260Arg (c.779A>G) pathogenic?

DPH5 p.His260Arg (c.779A>G) is classified Pathogenic/Likely pathogenic in DPH5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-31). AlphaMissense: likely pathogenic (0.9147); Very rare (popmax 0.00167%, amr); Associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.

How common is DPH5 p.His260Arg (c.779A>G) in the general population?

DPH5 p.His260Arg (c.779A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DPH5 p.His260Arg (c.779A>G)?

AlphaMissense predicts likely pathogenic (score 0.9147) — an in-silico prediction, not a clinical call.

DPH5 p.His260Arg

Q: What condition is associated with DPH5 p.His260Arg (c.779A>G)?

DPH5 p.His260Arg (c.779A>G) is associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (ClinVar).

c.779A>G · rs746680777 · VCV1708532

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties

Computational evidence

Protein change
AlphaMissense	0.9147	likely pathogenic ✓ concordant with ClinVar
REVEL	0.572	indeterminate
SaProt	LLR -14.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.15 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00112% 18/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
European (non-Finnish)	0.00144%	69,413

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: DPH5
Protein: p.His260Arg
Coding: c.779A>G
MANE Select: NM_015958
dbSNP: rs746680777
Type: single nucleotide variant
Location: chr1:100990487 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20
Residue 260: a UniProt-annotated variant site (in nedsff; loss of function in diphthamide biosynthesis shown in a yeast assay system); a UniProt-annotated variant site (in nedsff; results in multisystem abnormalities in a homozygous mouse knockin model; decreased function in diphthamide biosynthesis shown in a yeast assay system)

Full DPH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPH5 p.His260Gln Uncertain significance ★ ⚠ same residue
DPH5 p.Pro104Thr Uncertain significance ★★ ⚠ same condition
DPH5 c.260+1G>T Likely pathogenic ★ same condition
DPH5 p.Ala223Val Uncertain significance ★ ⚠ same condition
DPH5 p.Arg224Ser Uncertain significance ★ ⚠ same condition
DPH5 p.Leu163Pro Uncertain significance ★ ⚠ same condition
DPH5 p.Leu7Phe Uncertain significance ★ ⚠ same condition
DPH5 p.Leu94Val Uncertain significance ★ ⚠ same condition

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/dph5-p-his260arg (accessed [today's date]).

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