Is DRP2 p.Arg218His (c.653G>A) pathogenic?

DRP2 p.Arg218His (c.653G>A) is classified Conflicting classifications of pathogenicity in DRP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-02). AlphaMissense: ambiguous (0.3562); Ultra-rare (popmax 0.0459%, mid).

How common is DRP2 p.Arg218His (c.653G>A) in the general population?

DRP2 p.Arg218His (c.653G>A) is ultra-rare (popmax 0.0459%, mid) (gnomAD).

What do computational predictors say about DRP2 p.Arg218His (c.653G>A)?

AlphaMissense predicts ambiguous (score 0.3562) — an in-silico prediction, not a clinical call.

DRP2 p.Arg218His

c.653G>A · rs368516281 · VCV870772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0459%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3562	ambiguous
REVEL	0.259	benign-leaning
SaProt	LLR -8.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP -0.24, phastCons 1
Overall
CADD	23.4	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 0.0459% Middle Eastern · 2/4,355 alleles

Filtering AF 0.00812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0034%

Overall 0.001% 11/1,098,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0459%	2,178
African / African-American	0.00173%	57,757
European (non-Finnish)	0.000893%	111,941

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.Arg218His
Coding: c.653G>A
MANE Select: NM_001197293 · reported on NM_001939
dbSNP: rs368516281
Type: single nucleotide variant
Location: chrX:101241761 (GRCh38)
Structure: AlphaFold pLDDT 90.49 · 15 PDB

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

Similar variants

DRP2 p.Arg218Cys Uncertain significance ★ ⚠ same residue
DRP2 p.Glu432Ter Pathogenic ★★ same type
DPYSL2 p.Asn492Ser Uncertain significance ★★ ⚠ same type
DPYSL2 p.Asp520Asn Uncertain significance ★★ ⚠ same type
DRP2 p.Ala205Val Uncertain significance ★★ ⚠ same type
DRP2 p.Ala643Thr Uncertain significance ★★ ⚠ same type
DRP2 p.Arg199His Uncertain significance ★★ ⚠ same type
DRP2 p.Arg224Cys 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/drp2-p-arg218his (accessed [today's date]).

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