Is ELAC2 p.Leu628Pro (c.1883T>C) pathogenic?

ELAC2 p.Leu628Pro (c.1883T>C) is classified Uncertain significance in ELAC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.894); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ELAC2 p.Leu628Pro (c.1883T>C)?

ELAC2 p.Leu628Pro (c.1883T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ELAC2 p.Leu628Pro (c.1883T>C) in the general population?

ELAC2 p.Leu628Pro (c.1883T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ELAC2 p.Leu628Pro (c.1883T>C)?

AlphaMissense predicts likely pathogenic (score 0.894) — an in-silico prediction, not a clinical call.

ELAC2 p.Leu628Pro

c.1883T>C · VCV4248047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.894	likely pathogenic
REVEL	0.432	indeterminate
SaProt	LLR -16.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 25 kb · p 0.4 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,958 alleles

Overall 6.84e-05% 1/1,461,768 alleles · very rare

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.Leu628Pro
Coding: c.1883T>C
MANE Select: NM_018127
Type: single nucleotide variant
Location: chr17:12994988 (GRCh38)
Gene constraint: LOEUF 1.02 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.81 · 10 PDB
Residue 628: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ELAC2 p.Leu628= Likely benign ★ same residue
ELAC2 p.Glu482Ter Pathogenic/Likely pathogenic ★★ same condition
ELAC2 p.Ala344Thr Uncertain significance ★★ ⚠ same condition
ELAC2 p.Ala549Thr Uncertain significance ★★ ⚠ same condition
ELAC2 p.Arg104Cys Uncertain significance ★★ ⚠ same condition
ELAC2 p.Arg166Gly Uncertain significance ★★ ⚠ same condition
ELAC2 p.Arg381His Uncertain significance ★★ ⚠ same condition
ELAC2 p.Arg404His Uncertain significance ★★ ⚠ 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-leu628pro (accessed [today's date]).

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