Is ASNS p.Ser480Phe (c.1439C>T) pathogenic?

ASNS p.Ser480Phe (c.1439C>T) is classified Conflicting classifications of pathogenicity in ASNS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.8733); Very rare (popmax 0.00224%, eas); Associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.

How common is ASNS p.Ser480Phe (c.1439C>T) in the general population?

ASNS p.Ser480Phe (c.1439C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ASNS p.Ser480Phe (c.1439C>T)?

AlphaMissense predicts likely pathogenic (score 0.8733) — an in-silico prediction, not a clinical call.

ASNS p.Ser480Phe

Q: What condition is associated with ASNS p.Ser480Phe (c.1439C>T)?

ASNS p.Ser480Phe (c.1439C>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.1439C>T · rs754043007 · VCV242550

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.8733	likely pathogenic
REVEL	0.573	indeterminate
SaProt	LLR -15.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	34.0	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 0.00224% East Asian · 1/44,732 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000904%

Overall 0.00175% 28/1,595,878 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00487%	20,553
Finnishnot grpmax-eligible	0.0047%	21,263
East Asiangrpmax	0.00224%	44,732
European (non-Finnish)	0.0017%	58,717
African / African-American	0.00136%	73,640

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser480Phe
Coding: c.1439C>T
MANE Select: NM_001673
dbSNP: rs754043007
Type: single nucleotide variant
Location: chr7:97853097 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 480: the asparagine synthetase domain

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.Ser480= Likely benign ★ 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-ser480phe (accessed [today's date]).

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