Is ASNS p.Met290Thr (c.869T>C) pathogenic?

ASNS p.Met290Thr (c.869T>C) is classified Uncertain significance in ASNS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.4139); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ASNS p.Met290Thr (c.869T>C)?

ASNS p.Met290Thr (c.869T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ASNS p.Met290Thr (c.869T>C) in the general population?

ASNS p.Met290Thr (c.869T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ASNS p.Met290Thr (c.869T>C)?

AlphaMissense predicts ambiguous (score 0.4139) — an in-silico prediction, not a clinical call.

ASNS p.Met290Thr

c.869T>C · VCV4835795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4139	ambiguous
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 17 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	24.0	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 0.000339% European (non-Finnish) · 4/1,180,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,638 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,046
European (non-Finnish)grpmax	0.000339%	295,005

Finnish 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.Met290Thr
Coding: c.869T>C
MANE Select: NM_001673
Type: single nucleotide variant
Location: chr7:97858312 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 3 PDB
Residue 290: the asparagine synthetase domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASNS p.Met290Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ASNS p.Met290Leu Uncertain significance ⚠ same residue
ASNS c.1320+1G>C Likely pathogenic ★★ same condition
ASNS p.Arg465Ter Pathogenic/Likely pathogenic ★★ same condition
ASNS p.Arg550His Pathogenic/Likely pathogenic ★★ ⚠ same condition
ASNS c.1238+3A>G Uncertain significance ★★ same condition
ASNS p.Ala303Glu Uncertain significance ★★ ⚠ same condition
ASNS p.Arg251Gly Uncertain significance ★★ ⚠ 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-met290thr (accessed [today's date]).

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