Is IARS2 p.Pro370Ser (c.1108C>T) pathogenic?

IARS2 p.Pro370Ser (c.1108C>T) is classified Uncertain significance in IARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0806); Rare (popmax 0.164%, sas).

How common is IARS2 p.Pro370Ser (c.1108C>T) in the general population?

IARS2 p.Pro370Ser (c.1108C>T) is rare (popmax 0.164%, sas) (gnomAD).

What do computational predictors say about IARS2 p.Pro370Ser (c.1108C>T)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

IARS2 p.Pro370Ser

c.1108C>T · rs267598383 · VCV4804321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 53 kb · p 0.00075 · regional, not allelic
Overall
CADD	17.87	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 0.164% South Asian · 149/91,072 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00991% 160/1,614,078 alleles · rare exomes 153/1,461,816 · genomes 7/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.164%	611
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	8.47e-05%	1,179,972

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.Pro370Ser
Coding: c.1108C>T
MANE Select: NM_018060
dbSNP: rs267598383
Type: single nucleotide variant
Location: chr1:220105932 (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.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
IARS2 p.Ala701Val 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-pro370ser (accessed [today's date]).

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