Is ASNS p.Arg407Ter (c.1219C>T) pathogenic?

ASNS p.Arg407Ter (c.1219C>T) is classified Conflicting classifications of pathogenicity in ASNS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-25). Very rare (popmax 0.000593%, nfe); Associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.

How common is ASNS p.Arg407Ter (c.1219C>T) in the general population?

ASNS p.Arg407Ter (c.1219C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

ASNS p.Arg407Ter

Q: What condition is associated with ASNS p.Arg407Ter (c.1219C>T)?

ASNS p.Arg407Ter (c.1219C>T) is associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (ClinVar).

Q: How is Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1219C>T · rs1140424 · VCV2735059

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

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 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.2	GERP -1.6, phastCons 1
Overall
CADD	41.0	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) · 7/1,179,956 alleles

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

Overall 0.000479% 7/1,461,718 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: ASNS
Protein: p.Arg407Ter
Coding: c.1219C>T
MANE Select: NM_001673
dbSNP: rs1140424
Type: single nucleotide variant
Location: chr7:97854599 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 407: the asparagine synthetase domain; an α-helix

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

Disease context

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ASNS p.Arg407Gln Uncertain significance ★ ⚠ same residue
ASNS c.1030+1G>A Likely pathogenic ★★ same condition
ASNS c.1138-1G>A Likely pathogenic ★★ same condition
ASNS c.1239-2A>T Likely pathogenic ★★ same condition
ASNS c.1320+1G>C Likely pathogenic ★★ same condition
ASNS c.1320+1G>T Likely pathogenic ★★ same condition
ASNS c.1321-1G>A Likely pathogenic ★★ same condition
ASNS c.1476+1G>A 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/asns-p-arg407ter (accessed [today's date]).

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