Is ALS2 p.Ala1295= (c.3885G>A) pathogenic?

ALS2 p.Ala1295= (c.3885G>A) is classified Benign in ALS2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Low-frequency (popmax 4.73%, mid); Associated with ALS2-related disorder.

How common is ALS2 p.Ala1295= (c.3885G>A) in the general population?

ALS2 p.Ala1295= (c.3885G>A) is low-frequency (popmax 4.73%, mid) (gnomAD).

ALS2 p.Ala1295=

Q: What condition is associated with ALS2 p.Ala1295= (c.3885G>A)?

ALS2 p.Ala1295= (c.3885G>A) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

c.3885G>A · rs34946105 · VCV261374

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.73%, mid)

Conditions

ALS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -3.4
Overall
CADD	7.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.73% Middle Eastern · 287/6,062 alleles

Filtering AF 4.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.11%

Overall 3.16% 51,007/1,614,196 alleles · low-frequency exomes 46,968/1,461,874 · genomes 4,039/152,322 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	9.25%	11
Amishnot grpmax-eligible	6.03%	17
Finnishnot grpmax-eligible	4.79%	21
Middle Easterngrpmax	4.73%	21
South Asian	3.75%	27
Remaining individualsnot grpmax-eligible	3.35%	30
European (non-Finnish)	3.2%	31
Admixed American	1.95%	51
African / African-American	0.513%	195
East Asian	0.0134%	7,480

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1295=
Coding: c.3885G>A
MANE Select: NM_020919
dbSNP: rs34946105
Type: single nucleotide variant
Location: chr2:201715791 (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

Also linked: amyotrophic lateral sclerosis type 2, juvenile infantile-onset ascending hereditary spastic paralysis hereditary spastic paraplegia

Similar variants

ALS2 p.Ala1295Val 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 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter 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/als2-p-ala1295 (accessed [today's date]).

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