Is ASNS p.Ser455Phe (c.1364C>T) pathogenic?

ASNS p.Ser455Phe (c.1364C>T) is classified Conflicting classifications of pathogenicity in ASNS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2874); Rare (popmax 0.219%, nfe); Associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.

How common is ASNS p.Ser455Phe (c.1364C>T) in the general population?

ASNS p.Ser455Phe (c.1364C>T) is rare (popmax 0.219%, nfe) (gnomAD).

What do computational predictors say about ASNS p.Ser455Phe (c.1364C>T)?

AlphaMissense predicts likely benign (score 0.2874) — an in-silico prediction, not a clinical call.

ASNS p.Ser455Phe

Q: What condition is associated with ASNS p.Ser455Phe (c.1364C>T)?

ASNS p.Ser455Phe (c.1364C>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.1364C>T · rs61733327 · VCV729858

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2874 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.219%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.2874	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.78	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	21.7	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 0.219% European (non-Finnish) · 2,577/1,178,816 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.175% 2,819/1,611,122 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.219%	457
Remaining individualsnot grpmax-eligible	0.162%	618
Middle Eastern	0.149%	671
Admixed American	0.129%	773
African / African-American	0.0388%	2,580
Ashkenazi Jewishnot grpmax-eligible	0.0339%	2,950
Finnishnot grpmax-eligible	0.0141%	7,109
South Asian	0.00664%	15,059
East Asian	0.00223%	44,818

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.Ser455Phe
Coding: c.1364C>T
MANE Select: NM_001673
dbSNP: rs61733327
Type: single nucleotide variant
Location: chr7:97853172 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 455: the asparagine synthetase domain; a turn

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.Ser455= 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-ser455phe (accessed [today's date]).

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