Is ASNS p.Trp481Ser (c.1442G>C) pathogenic?

ASNS p.Trp481Ser (c.1442G>C) is classified Uncertain significance in ASNS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-31). AlphaMissense: likely pathogenic (0.9262); Absent from gnomAD v4.1; Associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.

How common is ASNS p.Trp481Ser (c.1442G>C) in the general population?

ASNS p.Trp481Ser (c.1442G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ASNS p.Trp481Ser (c.1442G>C)?

AlphaMissense predicts likely pathogenic (score 0.9262) — an in-silico prediction, not a clinical call.

ASNS p.Trp481Ser

Q: What condition is associated with ASNS p.Trp481Ser (c.1442G>C)?

ASNS p.Trp481Ser (c.1442G>C) 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.1442G>C · VCV4061946

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9262 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.9262	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -16.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 0.82, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ASNS
Protein: p.Trp481Ser
Coding: c.1442G>C
MANE Select: NM_001673
Type: single nucleotide variant
Location: chr7:97853094 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 481: 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.Trp481Ter Likely pathogenic ★ 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-trp481ser (accessed [today's date]).

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