Is DRP2 p.Pro558Ala (c.1672C>G) pathogenic?

DRP2 p.Pro558Ala (c.1672C>G) is classified Uncertain significance in DRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.3288); Ultra-rare (popmax 0.0325%, sas).

How common is DRP2 p.Pro558Ala (c.1672C>G) in the general population?

DRP2 p.Pro558Ala (c.1672C>G) is ultra-rare (popmax 0.0325%, sas) (gnomAD).

What do computational predictors say about DRP2 p.Pro558Ala (c.1672C>G)?

AlphaMissense predicts likely benign (score 0.3288) — an in-silico prediction, not a clinical call.

DRP2 p.Pro558Ala

c.1672C>G · rs778765111 · VCV3085833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3288 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3288	likely benign
REVEL	0.723	pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Overall
CADD	26.5	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 0.0325% South Asian · 18/55,440 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00183% 20/1,090,891 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0325%	3,080
Remaining individualsnot grpmax-eligible	0.00211%	47,337
European (non-Finnish)	0.000112%	891,178

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.Pro558Ala
Coding: c.1672C>G
MANE Select: NM_001197293 · reported on NM_001939
dbSNP: rs778765111
Type: single nucleotide variant
Location: chrX:101250554 (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.Pro558Leu 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-pro558ala (accessed [today's date]).

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