Is ALS2 p.Ile167Val (c.499A>G) pathogenic?

ALS2 p.Ile167Val (c.499A>G) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-07). AlphaMissense: likely benign (0.0633); Very rare (popmax 0.00549%, sas); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ile167Val (c.499A>G)?

ALS2 p.Ile167Val (c.499A>G) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ile167Val (c.499A>G) in the general population?

ALS2 p.Ile167Val (c.499A>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about ALS2 p.Ile167Val (c.499A>G)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

ALS2 p.Ile167Val

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.499A>G · rs575412396 · VCV1422977

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -5.17	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 1.4	GERP -0.9, phastCons 0.95
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	12.0	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 0.00549% South Asian · 5/91,062 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000558% 9/1,611,938 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,212
African / African-American	0.00267%	37,507
Remaining individualsnot grpmax-eligible	0.0016%	62,426
European (non-Finnish)	8.49e-05%	1,178,039

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.Ile167Val
Coding: c.499A>G
MANE Select: NM_020919
dbSNP: rs575412396
Type: single nucleotide variant
Location: chr2:201761495 (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

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

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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-ile167val (accessed [today's date]).

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