Is NARS1 p.Ala487Val (c.1460C>T) pathogenic?

NARS1 p.Ala487Val (c.1460C>T) is classified Likely pathogenic in NARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: likely benign (0.161); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities.

How common is NARS1 p.Ala487Val (c.1460C>T) in the general population?

NARS1 p.Ala487Val (c.1460C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NARS1 p.Ala487Val (c.1460C>T)?

AlphaMissense predicts likely benign (score 0.161) — an in-silico prediction, not a clinical call.

NARS1 p.Ala487Val

Q: What condition is associated with NARS1 p.Ala487Val (c.1460C>T)?

NARS1 p.Ala487Val (c.1460C>T) is associated with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (ClinVar).

c.1460C>T · VCV4538542

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.161 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities

Computational evidence

Protein change
AlphaMissense	0.161	likely benign ⚠ discordant with ClinVar
REVEL	0.371	indeterminate
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.93	donor gain · deltas
Pangolin	Δ0.83	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.34 · regional, not allelic
Overall
CADD	24.1	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

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: NARS1
Protein: p.Ala487Val
Coding: c.1460C>T
MANE Select: NM_004539
Type: single nucleotide variant
Location: chr18:57602410 (GRCh38)
Gene constraint: LOEUF 0.919 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.96 · 6 PDB
Residue 487: a UniProt-annotated variant site (in nedmilg); an α-helix

Full NARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NARS1 p.Arg439Ter Likely pathogenic ★★ same condition
NARS1 p.Arg534Ter Pathogenic/Likely pathogenic ★★ same condition
NARS1 p.Cys342Tyr Uncertain significance ★★ ⚠ same condition
NARS1 p.Arg322Leu Likely pathogenic ★ same condition
NARS1 p.Gln126Ter Likely pathogenic ★ same condition
NARS1 p.His403Leu Likely pathogenic ★ same condition
NARS1 c.493-1G>T Uncertain significance ★ same condition
NARS1 p.Ala216Ser 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/nars1-p-ala487val (accessed [today's date]).

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