Is DRP2 p.Leu649= (c.1947G>T) pathogenic?

DRP2 p.Leu649= (c.1947G>T) is classified Benign in DRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). Common (popmax 5.79%, mid) — too common for a highly-penetrant pathogenic allele.

DRP2 p.Leu649=

Q: How common is DRP2 p.Leu649= (c.1947G>T) in the general population?

DRP2 p.Leu649= (c.1947G>T) is common (popmax 5.79%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1947G>T · rs41304462 · VCV780713

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.79%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.4	GERP -0.77, phastCons 0.013
Overall
CADD	3.228	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.79% Middle Eastern · 251/4,335 alleles

Filtering AF 5.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.97%

Overall 1.08% 13,056/1,210,200 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	5.79%	17
African / African-American	2.22%	45
Ashkenazi Jewishnot grpmax-eligible	1.72%	58
Remaining individualsnot grpmax-eligible	1.52%	66
South Asian	1.24%	81
European (non-Finnish)	1.01%	99
East Asian	0.936%	107
Admixed American	0.789%	127
Finnishnot grpmax-eligible	0.0728%	1,374

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.Leu649=
Coding: c.1947G>T
MANE Select: NM_001197293 · reported on NM_001939
dbSNP: rs41304462
Type: single nucleotide variant
Location: chrX:101252686 (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.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
DRP2 p.Arg224His 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-leu649 (accessed [today's date]).

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