Is DRP2 p.Arg224His (c.671G>A) pathogenic?

DRP2 p.Arg224His (c.671G>A) is classified Uncertain significance in DRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1646); Very rare (popmax 0.00352%, sas).

How common is DRP2 p.Arg224His (c.671G>A) in the general population?

DRP2 p.Arg224His (c.671G>A) is very rare (popmax 0.00352%, sas) (gnomAD).

What do computational predictors say about DRP2 p.Arg224His (c.671G>A)?

AlphaMissense predicts likely benign (score 0.1646) — an in-silico prediction, not a clinical call.

DRP2 p.Arg224His

c.671G>A · rs748759701 · VCV1393781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1646	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.16	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 5.9	GERP 1.7, phastCons 1
Overall
CADD	24.1	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 0.00352% South Asian · 2/56,786 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00207% 25/1,209,895 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00352%	28,393
African / African-American	0.0035%	28,553
European (non-Finnish)	0.00235%	42,634

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.Arg224His
Coding: c.671G>A
MANE Select: NM_001197293 · reported on NM_001939
dbSNP: rs748759701
Type: single nucleotide variant
Location: chrX:101241779 (GRCh38)
Structure: AlphaFold pLDDT 90.49 · 15 PDB
Residue 224: an α-helix

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

Similar variants

DRP2 p.Arg224Cys 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.Arg228Trp 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-arg224his (accessed [today's date]).

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