Is DRP2 p.Ser889Leu (c.2666C>T) pathogenic?

DRP2 p.Ser889Leu (c.2666C>T) is classified Uncertain significance in DRP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0847); Ultra-rare (popmax 0.0284%, amr).

How common is DRP2 p.Ser889Leu (c.2666C>T) in the general population?

DRP2 p.Ser889Leu (c.2666C>T) is ultra-rare (popmax 0.0284%, amr) (gnomAD).

What do computational predictors say about DRP2 p.Ser889Leu (c.2666C>T)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

DRP2 p.Ser889Leu

c.2666C>T · rs34562102 · VCV1388458

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 0.56, phastCons 1
Overall
CADD	24.5	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 0.0284% Admixed American · 13/45,774 alleles

Filtering AF 0.0201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.0193% 233/1,209,539 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0284%	3,521
European (non-Finnish)	0.0227%	4,409
Remaining individualsnot grpmax-eligible	0.021%	4,762
South Asian	0.00705%	14,186
African / African-American	0.00351%	28,513
Finnishnot grpmax-eligible	0.00215%	46,558

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.Ser889Leu
Coding: c.2666C>T
MANE Select: NM_001197293 · reported on NM_001939
dbSNP: rs34562102
Type: single nucleotide variant
Location: chrX:101260086 (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.Ser889= Likely benign ★ 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-ser889leu (accessed [today's date]).

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