Is ALS2 p.Val368Met (c.1102G>A) pathogenic?

ALS2 p.Val368Met (c.1102G>A) is classified Benign in ALS2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0696); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with ALS2-related disorder.

What condition is associated with ALS2 p.Val368Met (c.1102G>A)?

ALS2 p.Val368Met (c.1102G>A) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis (ClinVar).

What do computational predictors say about ALS2 p.Val368Met (c.1102G>A)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

ALS2 p.Val368Met

Q: How common is ALS2 p.Val368Met (c.1102G>A) in the general population?

ALS2 p.Val368Met (c.1102G>A) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1102G>A · rs3219156 · VCV261364

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -8.06	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 -7.1	GERP -3.7
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	0.005	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 100% East Asian · 44,827/44,848 alleles

Filtering AF 99.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.9%

Overall 90.2% 1,454,645/1,612,470 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
South Asian	94.8%	1
Amishnot grpmax-eligible	94.1%	1
Admixed American	92.5%	1
Finnishnot grpmax-eligible	92.2%	1
Ashkenazi Jewishnot grpmax-eligible	90.2%	1
Remaining individualsnot grpmax-eligible	90.2%	1
European (non-Finnish)	90%	1
Middle Eastern	87.6%	1
African / African-American	78.9%	1

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.Val368Met
Coding: c.1102G>A
MANE Select: NM_020919
dbSNP: rs3219156
Type: single nucleotide variant
Location: chr2:201760892 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 368: a UniProt-annotated variant site (in)

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

Disease context

Also linked: amyotrophic lateral sclerosis type 2, juvenile juvenile primary lateral sclerosis infantile-onset ascending hereditary spastic paralysis

Similar variants

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 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

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-val368met (accessed [today's date]).

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