Is ELAC2 p.Ile396Val (c.1186A>G) pathogenic?

ELAC2 p.Ile396Val (c.1186A>G) is classified Uncertain significance in ELAC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.1007); Rare (popmax 0.103%, afr); Associated with combined oxidative phosphorylation defect type 17.

What condition is associated with ELAC2 p.Ile396Val (c.1186A>G)?

ELAC2 p.Ile396Val (c.1186A>G) is associated with combined oxidative phosphorylation defect type 17, prostate cancer, hereditary, 2 (ClinVar).

How common is ELAC2 p.Ile396Val (c.1186A>G) in the general population?

ELAC2 p.Ile396Val (c.1186A>G) is rare (popmax 0.103%, afr) (gnomAD).

What do computational predictors say about ELAC2 p.Ile396Val (c.1186A>G)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

ELAC2 p.Ile396Val

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.1186A>G · rs149544601 · VCV541491

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined oxidative phosphorylation defect type 17

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 25 kb · p 0.4 · regional, not allelic
Overall
CADD	22.4	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 0.103% African / African-American · 77/75,000 alleles

Filtering AF 0.0841% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0774%

Overall 0.00627% 101/1,610,078 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.103%	974
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0112%	8,913
Admixed American	0.00675%	14,810
South Asian	0.00553%	18,076
East Asian	0.00223%	44,832
European (non-Finnish)	0.000509%	196,325

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.Ile396Val
Coding: c.1186A>G
MANE Select: NM_018127
dbSNP: rs149544601
Type: single nucleotide variant
Location: chr17:13002473 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81 · 10 PDB
Residue 396: a turn

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

Also linked: prostate cancer, hereditary, 2

For Combined oxidative phosphorylation defect type 17 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ELAC2 p.Ile396Phe 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
ELAC2 p.Glu30Ter Pathogenic/Likely 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-ile396val (accessed [today's date]).

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