Is ELAC2 p.Arg643Gln (c.1928G>A) pathogenic?

ELAC2 p.Arg643Gln (c.1928G>A) is classified Uncertain significance in ELAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). AlphaMissense: likely benign (0.0955); Rare (popmax 0.187%, eas); Associated with combined oxidative phosphorylation defect type 17.

What condition is associated with ELAC2 p.Arg643Gln (c.1928G>A)?

ELAC2 p.Arg643Gln (c.1928G>A) is associated with combined oxidative phosphorylation defect type 17 (ClinVar).

How common is ELAC2 p.Arg643Gln (c.1928G>A) in the general population?

ELAC2 p.Arg643Gln (c.1928G>A) is rare (popmax 0.187%, eas) (gnomAD).

What do computational predictors say about ELAC2 p.Arg643Gln (c.1928G>A)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

ELAC2 p.Arg643Gln

Q: How is Combined oxidative phosphorylation defect type 17 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1928G>A · rs199545091 · VCV1443741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.187%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 17

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.55	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 25 kb · p 0.4 · regional, not allelic
Overall
CADD	32.0	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 0.187% East Asian · 84/44,872 alleles

Filtering AF 0.155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.143%

Overall 0.00657% 106/1,614,084 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.187%	534
Admixed American	0.0117%	8,575
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.00266%	37,526
South Asian	0.0022%	45,538
Finnishnot grpmax-eligible	0.00156%	63,920
European (non-Finnish)	0.000593%	168,578

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: ELAC2
Protein: p.Arg643Gln
Coding: c.1928G>A
MANE Select: NM_018127
dbSNP: rs199545091
Type: single nucleotide variant
Location: chr17:12994865 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81 · 10 PDB
Residue 643: a β-strand

Full ELAC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 17 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ELAC2 p.Arg643Leu Uncertain significance ★ ⚠ same residue
ELAC2 p.Arg643Trp Uncertain significance ★ ⚠ same residue
ELAC2 c.1080-1G>C Likely pathogenic ★★ same condition
ELAC2 c.1423+1G>A Pathogenic ★★ same condition
ELAC2 c.1908+1G>A Likely pathogenic ★★ same condition
ELAC2 c.245+2T>A Pathogenic/Likely pathogenic ★★ same condition
ELAC2 p.Arg497Ter Pathogenic/Likely pathogenic ★★ same condition
ELAC2 p.Gln18Ter Pathogenic ★★ same condition

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/elac2-p-arg643gln (accessed [today's date]).

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