Is ALS2 p.Lys975Glu (c.2923A>G) pathogenic?

ALS2 p.Lys975Glu (c.2923A>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely pathogenic (0.6672); Very rare (popmax 0.00669%, eas); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Lys975Glu (c.2923A>G)?

ALS2 p.Lys975Glu (c.2923A>G) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Lys975Glu (c.2923A>G) in the general population?

ALS2 p.Lys975Glu (c.2923A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ALS2 p.Lys975Glu (c.2923A>G)?

AlphaMissense predicts likely pathogenic (score 0.6672) — an in-silico prediction, not a clinical call.

ALS2 p.Lys975Glu

Q: How is Infantile-onset ascending hereditary spastic paralysis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2923A>G · rs770482791 · VCV2178425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.6672	likely pathogenic
REVEL	0.189	benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,866 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000205% 3/1,461,358 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: ALS2
Protein: p.Lys975Glu
Coding: c.2923A>G
MANE Select: NM_020919
dbSNP: rs770482791
Type: single nucleotide variant
Location: chr2:201727268 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 975: the ph domain

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

Disease context

infantile-onset ascending hereditary spastic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile-onset ascending hereditary spastic paralysis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Lys975= Likely benign ★ 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
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1461Ter 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-lys975glu (accessed [today's date]).

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