Is NARS2 p.Ser439Pro (c.1315T>C) pathogenic?

NARS2 p.Ser439Pro (c.1315T>C) is classified Uncertain significance in NARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-02). AlphaMissense: likely pathogenic (0.5796); Ultra-rare (popmax 0.0467%, amr); Associated with Inborn genetic diseases.

What condition is associated with NARS2 p.Ser439Pro (c.1315T>C)?

NARS2 p.Ser439Pro (c.1315T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NARS2 p.Ser439Pro (c.1315T>C) in the general population?

NARS2 p.Ser439Pro (c.1315T>C) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about NARS2 p.Ser439Pro (c.1315T>C)?

AlphaMissense predicts likely pathogenic (score 0.5796) — an in-silico prediction, not a clinical call.

NARS2 p.Ser439Pro

c.1315T>C · rs775587143 · VCV1979094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5796	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -13.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 138 kb · p 0.076 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Admixed American · 28/60,012 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.00248% 40/1,614,112 alleles · ultra-rare exomes 32/1,461,842 · genomes 8/152,270 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,143
African / African-American	0.00267%	37,474
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000763%	131,115

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: NARS2
Protein: p.Ser439Pro
Coding: c.1315T>C
MANE Select: NM_024678
dbSNP: rs775587143
Type: single nucleotide variant
Location: chr11:78436789 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.59
Residue 439: a UniProt-annotated variant site (in coxpd24)

Full NARS2 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

NARS2 p.Ala17Val Uncertain significance ★★ ⚠ same condition
NARS2 p.Arg243Gln Uncertain significance ★★ ⚠ same condition
NARS2 p.Arg436Gln Uncertain significance ★★ ⚠ same condition
NARS2 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
NARS2 p.Asn461Ser Uncertain significance ★★ ⚠ same condition
NARS2 p.Glu416Gln Uncertain significance ★★ ⚠ same condition
NARS2 p.His413Asp Uncertain significance ★★ ⚠ same condition
NARS2 p.Ile115Val 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/nars2-p-ser439pro (accessed [today's date]).

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