Is ALS2 p.Arg501Trp (c.1501C>T) pathogenic?

ALS2 p.Arg501Trp (c.1501C>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-07). AlphaMissense: likely pathogenic (0.6542); Ultra-rare (popmax 0.0493%, mid).

How common is ALS2 p.Arg501Trp (c.1501C>T) in the general population?

ALS2 p.Arg501Trp (c.1501C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about ALS2 p.Arg501Trp (c.1501C>T)?

AlphaMissense predicts likely pathogenic (score 0.6542) — an in-silico prediction, not a clinical call.

ALS2 p.Arg501Trp

c.1501C>T · VCV3730952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6542	likely pathogenic
REVEL	0.303	indeterminate
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	23.9	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.0013% 21/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.00267%	37,452
South Asian	0.0022%	45,547
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.0011%	90,770

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.Arg501Trp
Coding: c.1501C>T
MANE Select: NM_020919
Type: single nucleotide variant
Location: chr2:201754642 (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 p.Arg501Gln Uncertain significance ★ ⚠ same residue
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

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-arg501trp (accessed [today's date]).

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