Is ALS2 p.Leu216Val (c.646C>G) pathogenic?

ALS2 p.Leu216Val (c.646C>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.1176); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Leu216Val (c.646C>G)?

ALS2 p.Leu216Val (c.646C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ALS2 p.Leu216Val (c.646C>G) in the general population?

ALS2 p.Leu216Val (c.646C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALS2 p.Leu216Val (c.646C>G)?

AlphaMissense predicts likely benign (score 0.1176) — an in-silico prediction, not a clinical call.

ALS2 p.Leu216Val

c.646C>G · VCV3859910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1176 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1176	likely benign
REVEL	0.507	indeterminate
SaProt	LLR -8.10	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	26.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALS2
Protein: p.Leu216Val
Coding: c.646C>G
MANE Select: NM_020919
Type: single nucleotide variant
Location: chr2:201761348 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69

Full ALS2 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

ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala333Ser Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala377Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala402Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1329Trp Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1330His Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1405Cys Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1461Gln 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/als2-p-leu216val (accessed [today's date]).

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