Is ALS2 p.Ser987= (c.2961A>G) pathogenic?

ALS2 p.Ser987= (c.2961A>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.0011%, sas); Associated with ALS2-related disorder.

What condition is associated with ALS2 p.Ser987= (c.2961A>G)?

ALS2 p.Ser987= (c.2961A>G) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Ser987= (c.2961A>G) in the general population?

ALS2 p.Ser987= (c.2961A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

ALS2 p.Ser987=

c.2961A>G · rs780301796 · VCV896523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

ALS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.059	GERP 0.33, phastCons 0.84
Overall
CADD	8.858	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 0.000124% 2/1,613,766 alleles · very rare exomes 2/1,461,514 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.48e-05%	1,179,672

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.Ser987=
Coding: c.2961A>G
MANE Select: NM_020919
dbSNP: rs780301796
Type: single nucleotide variant
Location: chr2:201727230 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 987: the ph domain

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: amyotrophic lateral sclerosis type 2, juvenile

Similar variants

ALS2 c.2580+2T>C 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
ALS2 p.Arg1461Ter Pathogenic ★★ same condition
ALS2 p.Arg1510Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg201Ter 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-ser987 (accessed [today's date]).

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