Is ALS2 p.Ala199Val (c.596C>T) pathogenic?

ALS2 p.Ala199Val (c.596C>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). AlphaMissense: likely benign (0.1725); Very rare (popmax 0.0022%, sas).

How common is ALS2 p.Ala199Val (c.596C>T) in the general population?

ALS2 p.Ala199Val (c.596C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ALS2 p.Ala199Val (c.596C>T)?

AlphaMissense predicts likely benign (score 0.1725) — an in-silico prediction, not a clinical call.

ALS2 p.Ala199Val

c.596C>T · rs576502295 · VCV2578894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1725	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	25.0	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 0.0022% South Asian · 2/90,972 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,611,046 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,486
African / African-American	0.00134%	74,846
European (non-Finnish)	8.49e-05%	1,177,648

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.Ala199Val
Coding: c.596C>T
MANE Select: NM_020919
dbSNP: rs576502295
Type: single nucleotide variant
Location: chr2:201761398 (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

Similar variants

ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same type
ALS2 c.2580+2T>C Pathogenic ★★ same type
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same type
ALS2 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Ala573Glu Likely pathogenic ★★ same type
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same type
ALS2 p.Arg1461Ter Pathogenic ★★ same type

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-ala199val (accessed [today's date]).

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