Is ALS2 p.Pro1016Arg (c.3047C>G) pathogenic?

ALS2 p.Pro1016Arg (c.3047C>G) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.1136); Very rare (popmax 0.00314%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Pro1016Arg (c.3047C>G)?

ALS2 p.Pro1016Arg (c.3047C>G) is associated with Inborn genetic diseases, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Pro1016Arg (c.3047C>G) in the general population?

ALS2 p.Pro1016Arg (c.3047C>G) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Pro1016Arg (c.3047C>G)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

ALS2 p.Pro1016Arg

c.3047C>G · rs776807292 · VCV1372313

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	13.51	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 0.00314% European (non-Finnish) · 37/1,180,000 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00274% 40/1,461,866 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,892
South Asian	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: ALS2
Protein: p.Pro1016Arg
Coding: c.3047C>G
MANE Select: NM_020919
dbSNP: rs776807292
Type: single nucleotide variant
Location: chr2:201726799 (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

Also linked: infantile-onset ascending hereditary spastic paralysis

Similar variants

ALS2 p.Pro1016Leu Uncertain significance ★★ ⚠ same residue
ALS2 p.Pro1016Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
ALS2 p.Pro1016His Uncertain significance ★ ⚠ same residue
ALS2 p.Pro1016Thr Uncertain significance ★ ⚠ same residue
ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu 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/als2-p-pro1016arg (accessed [today's date]).

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