Is ALS2 p.Val468Ala (c.1403T>C) pathogenic?

ALS2 p.Val468Ala (c.1403T>C) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: likely benign (0.3016); Very rare (popmax 0.0089%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Val468Ala (c.1403T>C)?

ALS2 p.Val468Ala (c.1403T>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia (ClinVar).

How common is ALS2 p.Val468Ala (c.1403T>C) in the general population?

ALS2 p.Val468Ala (c.1403T>C) is very rare (popmax 0.0089%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Val468Ala (c.1403T>C)?

AlphaMissense predicts likely benign (score 0.3016) — an in-silico prediction, not a clinical call.

ALS2 p.Val468Ala

c.1403T>C · rs751794543 · VCV1344310

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3016 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3016	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.09	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 96 bp · p 4.8e-05 · regional, not allelic
Overall
CADD	19.56	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 0.0089% European (non-Finnish) · 105/1,179,998 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.007%

Overall 0.00663% 107/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,238
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Val468Ala
Coding: c.1403T>C
MANE Select: NM_020919
dbSNP: rs751794543
Type: single nucleotide variant
Location: chr2:201757470 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 468: the 'disordered' region

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: hereditary spastic paraplegia

Similar variants

ALS2 p.Val468Met Uncertain significance ★ ⚠ same residue
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala333Ser Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala377Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Ala402Thr Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1329Trp Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1330His Uncertain significance ★★ ⚠ same condition
ALS2 p.Arg1341His Uncertain significance ★★ ⚠ 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-val468ala (accessed [today's date]).

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