Is DRP2 p.Arg457His (c.1370G>A) pathogenic?

DRP2 p.Arg457His (c.1370G>A) is classified Uncertain significance in DRP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-17). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.00176%, sas); Associated with DRP2-related disorder.

What condition is associated with DRP2 p.Arg457His (c.1370G>A)?

DRP2 p.Arg457His (c.1370G>A) is associated with DRP2-related disorder (ClinVar).

How common is DRP2 p.Arg457His (c.1370G>A) in the general population?

DRP2 p.Arg457His (c.1370G>A) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about DRP2 p.Arg457His (c.1370G>A)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

DRP2 p.Arg457His

c.1370G>A · VCV3358298

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DRP2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -9.17	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 12	GERP 1.7, phastCons 1
Overall
CADD	23.8	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 0.00176% South Asian · 1/56,978 alleles

Overall 9.11e-05% 1/1,098,047 alleles · very rare

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: DRP2
Protein: p.Arg457His
Coding: c.1370G>A
MANE Select: NM_001197293 · reported on NM_001939
Type: single nucleotide variant
Location: chrX:101248206 (GRCh38)
Structure: AlphaFold pLDDT 90.49 · 15 PDB

Full DRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DRP2-related disorder

Similar variants

DRP2 p.Arg457Cys Uncertain significance ★★ ⚠ same residue
DPYSL2 p.Pro457Leu Uncertain significance ★ ⚠ same residue
DPYSL2 p.Asp520Asn Uncertain significance ★★ ⚠ same condition
DRP2 p.Gln336Ter Conflicting classifications of pathogenicity ★ same condition
DRP2 p.His758Gln Uncertain significance ★ ⚠ same condition
DRP2 p.Thr672Ala Uncertain significance ★ ⚠ same condition
DPYSL2 p.Asp308Asn Uncertain significance ⚠ same condition
DPYSL2 p.Arg278His Likely benign ⚠ 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/drp2-p-arg457his (accessed [today's date]).

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