Is ALS2 p.Arg704Ter (c.2110C>T) pathogenic?

ALS2 p.Arg704Ter (c.2110C>T) is classified Pathogenic in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-07). Very rare (popmax 0.000593%, nfe).

How common is ALS2 p.Arg704Ter (c.2110C>T) in the general population?

ALS2 p.Arg704Ter (c.2110C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

ALS2 p.Arg704Ter

c.2110C>T · rs748568886 · VCV2444743

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 34
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.7, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,980 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,826 alleles · very rare

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.Arg704Ter
Coding: c.2110C>T
MANE Select: NM_020919
dbSNP: rs748568886
Type: single nucleotide variant
Location: chr2:201744318 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 704: the dh domain

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

Similar variants

ALS2 p.Arg704Gln 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-arg704ter (accessed [today's date]).

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