Is IARS2 p.Pro690Ser (c.2068C>T) pathogenic?

IARS2 p.Pro690Ser (c.2068C>T) is classified Uncertain significance in IARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.1049); Very rare (popmax 6.2e-05%).

How common is IARS2 p.Pro690Ser (c.2068C>T) in the general population?

IARS2 p.Pro690Ser (c.2068C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about IARS2 p.Pro690Ser (c.2068C>T)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

IARS2 p.Pro690Ser

c.2068C>T · VCV4074575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 53 kb · p 0.00075 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 6.2e-05%

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 1/1,461,864 · genomes 0/152,244 · joint denominator

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.Pro690Ser
Coding: c.2068C>T
MANE Select: NM_018060
Type: single nucleotide variant
Location: chr1:220137936 (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

Similar variants

IARS2 p.Pro690= Likely benign ★ same residue
IARS2 p.Arg817His Pathogenic/Likely pathogenic ★★ ⚠ same type
IARS2 p.Tyr117Ter Pathogenic/Likely pathogenic ★★ same type
IARS2 c.550+6T>A Uncertain significance ★★ same type
IARS2 p.Ala12Thr Uncertain significance ★★ ⚠ same type
IARS2 p.Ala338Val Uncertain significance ★★ ⚠ same type
IARS2 p.Ala492Val Uncertain significance ★★ ⚠ same type
IARS2 p.Ala587Thr Uncertain significance ★★ ⚠ same type

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-pro690ser (accessed [today's date]).

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