Is IARS2 p.Ser462Arg (c.1386C>G) pathogenic?

IARS2 p.Ser462Arg (c.1386C>G) is classified Uncertain significance in IARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: likely pathogenic (0.8342); Very rare (popmax 0.00263%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IARS2 p.Ser462Arg (c.1386C>G)?

IARS2 p.Ser462Arg (c.1386C>G) is associated with Inborn genetic diseases (ClinVar).

How common is IARS2 p.Ser462Arg (c.1386C>G) in the general population?

IARS2 p.Ser462Arg (c.1386C>G) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about IARS2 p.Ser462Arg (c.1386C>G)?

AlphaMissense predicts likely pathogenic (score 0.8342) — an in-silico prediction, not a clinical call.

IARS2 p.Ser462Arg

c.1386C>G · rs758799350 · VCV3107832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8342	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.78	GERP -0.53, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 53 kb · p 0.00075 · regional, not allelic
Overall
CADD	22.9	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 0.00263% European (non-Finnish) · 31/1,179,128 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00198% 32/1,612,836 alleles · very rare exomes 31/1,460,824 · genomes 1/152,012 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,036
Remaining individualsnot grpmax-eligible	0.0016%	62,420

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: IARS2
Protein: p.Ser462Arg
Coding: c.1386C>G
MANE Select: NM_018060
dbSNP: rs758799350
Type: single nucleotide variant
Location: chr1:220110844 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.77

Full IARS2 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

IARS2 c.550+6T>A Uncertain significance ★★ same condition
IARS2 p.Ala338Val Uncertain significance ★★ ⚠ same condition
IARS2 p.Ala492Val Uncertain significance ★★ ⚠ same condition
IARS2 p.Ala587Thr Uncertain significance ★★ ⚠ same condition
IARS2 p.Ala878Thr Uncertain significance ★★ ⚠ same condition
IARS2 p.Ala936Thr Uncertain significance ★★ ⚠ same condition
IARS2 p.Arg185Lys Uncertain significance ★★ ⚠ same condition
IARS2 p.Arg185Ser 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/iars2-p-ser462arg (accessed [today's date]).

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