Is YARS2 p.Pro397Ser (c.1189C>T) pathogenic?

YARS2 p.Pro397Ser (c.1189C>T) is classified Likely benign in YARS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-14). AlphaMissense: likely benign (0.0761); Ultra-rare (popmax 0.0659%, sas); Associated with Inborn genetic diseases.

What condition is associated with YARS2 p.Pro397Ser (c.1189C>T)?

YARS2 p.Pro397Ser (c.1189C>T) is associated with Inborn genetic diseases (ClinVar).

How common is YARS2 p.Pro397Ser (c.1189C>T) in the general population?

YARS2 p.Pro397Ser (c.1189C>T) is ultra-rare (popmax 0.0659%, sas) (gnomAD).

What do computational predictors say about YARS2 p.Pro397Ser (c.1189C>T)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

YARS2 p.Pro397Ser

c.1189C>T · rs779176806 · VCV2524321

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -9.88	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 0.58	phastCons 0.9
Regional constraint	o/e 1.00	unconstrained · MANE · 8,667 bp · p 0.93 · regional, not allelic
Overall
CADD	14.91	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 0.0659% South Asian · 60/91,082 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0476%

Overall 0.00421% 68/1,613,922 alleles · ultra-rare exomes 66/1,461,822 · genomes 2/152,100 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0659%	1,518
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.00267%	37,446
East Asian	0.00223%	44,888

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: YARS2
Protein: p.Pro397Ser
Coding: c.1189C>T
MANE Select: NM_001040436
dbSNP: rs779176806
Type: single nucleotide variant
Location: chr12:32750022 (GRCh38)
Gene constraint: LOEUF 1.035 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.57 · 2 PDB

Full YARS2 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

YARS2 p.Ala139Val Uncertain significance ★★ ⚠ same condition
YARS2 p.Ala31Thr Uncertain significance ★★ ⚠ same condition
YARS2 p.Ala31Val Uncertain significance ★★ ⚠ same condition
YARS2 p.Ala396Gly Uncertain significance ★★ same condition
YARS2 p.Ala94Thr Uncertain significance ★★ ⚠ same condition
YARS2 p.Arg118Leu Uncertain significance ★★ ⚠ same condition
YARS2 p.Arg136Cys Uncertain significance ★★ ⚠ same condition
YARS2 p.Gln36Arg 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/yars2-p-pro397ser (accessed [today's date]).

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