Is DPH2 p.Arg463His (c.1388G>A) pathogenic?

DPH2 p.Arg463His (c.1388G>A) is classified Uncertain significance in DPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.0634); Very rare (popmax 0.0022%, sas).

How common is DPH2 p.Arg463His (c.1388G>A) in the general population?

DPH2 p.Arg463His (c.1388G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DPH2 p.Arg463His (c.1388G>A)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

DPH2 p.Arg463His

c.1388G>A · rs761290368 · VCV3085472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP 0.48
Regional constraint	o/e 0.97	unconstrained · MANE · 603 bp · p 0.64 · regional, not allelic
Overall
CADD	16.55	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000743% 12/1,614,218 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,512
African / African-American	0.00133%	75,052
European (non-Finnish)	0.000678%	147,505

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.Arg463His
Coding: c.1388G>A
MANE Select: NM_001384
dbSNP: rs761290368
Type: single nucleotide variant
Location: chr1:43972457 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.60
Residue 463: 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

Similar variants

DPH2 p.Arg463Gly Uncertain significance ★ ⚠ same residue
DPH2 p.Arg201His Uncertain significance ★★ ⚠ same type
DPH2 p.Arg477Ter Likely pathogenic ★ same type
DPH2 p.Ser75Ter Likely pathogenic ★ same type
DPH2 p.Ala310Val Uncertain significance ★ ⚠ same type
DPH2 p.Ala345Thr Uncertain significance ★ ⚠ same type
DPH2 p.Ala448Thr Uncertain significance ★ ⚠ same type
DPH2 p.Arg125His 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-arg463his (accessed [today's date]).

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