Is ASNS p.Phe362Val (c.1084T>G) pathogenic?

ASNS p.Phe362Val (c.1084T>G) is classified Pathogenic/Likely pathogenic in ASNS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-29). AlphaMissense: likely pathogenic (0.7241); Ultra-rare (popmax 0.0351%, mid); Associated with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.

How common is ASNS p.Phe362Val (c.1084T>G) in the general population?

ASNS p.Phe362Val (c.1084T>G) is ultra-rare (popmax 0.0351%, mid) (gnomAD).

What do computational predictors say about ASNS p.Phe362Val (c.1084T>G)?

AlphaMissense predicts likely pathogenic (score 0.7241) — an in-silico prediction, not a clinical call.

ASNS p.Phe362Val

Q: What condition is associated with ASNS p.Phe362Val (c.1084T>G)?

ASNS p.Phe362Val (c.1084T>G) 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.1084T>G · rs398122973 · VCV91840

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7241 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.7241	likely pathogenic ✓ concordant with ClinVar
REVEL	0.597	indeterminate
SaProt	LLR -11.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	28.3	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 0.0351% Middle Eastern · 2/5,696 alleles

Filtering AF 0.00616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000205% 3/1,460,494 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0351%	2,848
Remaining individualsnot grpmax-eligible	0.0016%	62,422

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.Phe362Val
Coding: c.1084T>G
MANE Select: NM_001673
dbSNP: rs398122973
Type: single nucleotide variant
Location: chr7:97855406 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 362: a UniProt-annotated variant site (in asnsd; dramatic reduction in protein abundance); the asparagine synthetase domain; a β-strand

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 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
ASNS c.1476+2T>C 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/asns-p-phe362val (accessed [today's date]).

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