Is SETX p.Asn620Asp (c.1858A>G) pathogenic?

SETX p.Asn620Asp (c.1858A>G) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-06). AlphaMissense: likely benign (0.08); Very rare (popmax 0.00492%, nfe); Associated with Inborn genetic diseases.

How common is SETX p.Asn620Asp (c.1858A>G) in the general population?

SETX p.Asn620Asp (c.1858A>G) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about SETX p.Asn620Asp (c.1858A>G)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

SETX p.Asn620Asp

Q: What condition is associated with SETX p.Asn620Asp (c.1858A>G)?

SETX p.Asn620Asp (c.1858A>G) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.1858A>G · rs777081940 · VCV1256249

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -6.82	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 0.011	GERP -0.15
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	6.541	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 0.00492% European (non-Finnish) · 58/1,180,028 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00378% 61/1,614,032 alleles · very rare exomes 60/1,461,810 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,345
African / African-American	0.00267%	37,464
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: SETX
Protein: p.Asn620Asp
Coding: c.1858A>G
MANE Select: NM_015046
dbSNP: rs777081940
Type: single nucleotide variant
Location: chr9:132329740 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93

Full SETX 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: amyotrophic lateral sclerosis type 4 spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same condition
SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Arg1606Ter Pathogenic ★★ same condition
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg2098Ter Pathogenic ★★ same condition
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1695Ter Pathogenic/Likely 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/setx-p-asn620asp (accessed [today's date]).

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