Is AAR2 p.Val174Met (c.520G>A) pathogenic?

AAR2 p.Val174Met (c.520G>A) is classified Likely pathogenic in AAR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-01-10). AlphaMissense: likely benign (0.102); Ultra-rare (popmax 0.099%, mid); Associated with ventricular septal defect.

What condition is associated with AAR2 p.Val174Met (c.520G>A)?

AAR2 p.Val174Met (c.520G>A) is associated with ventricular septal defect, microcephaly, patent foramen ovale (ClinVar).

How common is AAR2 p.Val174Met (c.520G>A) in the general population?

AAR2 p.Val174Met (c.520G>A) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about AAR2 p.Val174Met (c.520G>A)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

AAR2 p.Val174Met

c.520G>A · rs746800707 · VCV242897

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ventricular septal defect

Computational evidence

Protein change
AlphaMissense	0.102	likely benign ⚠ discordant with ClinVar
REVEL	0.168	moderately benign-leaning
SaProt	LLR -7.53	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 0.3	GERP -5.2
Regional constraint	o/e 0.88	unconstrained · MANE · 16 kb · p 0.0057 · regional, not allelic
Overall
CADD	13.15	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 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.0026% 42/1,614,244 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
African / African-American	0.0253%	3,950
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.0022%	45,544
Admixed American	0.00167%	60,034
European (non-Finnish)	0.000593%	168,579

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: AAR2
Protein: p.Val174Met
Coding: c.520G>A
MANE Select: NM_001271874
dbSNP: rs746800707
Type: single nucleotide variant
Location: chr20:36240388 (GRCh38)
Gene constraint: LOEUF 1.472 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.74 · 1 PDB

Full AAR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ventricular septal defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly patent foramen ovale

Similar variants

AAR2 p.Val174Gly Uncertain significance ★ ⚠ same residue
AAR2 p.Ala365Thr Likely benign ★★ ⚠ same type
AAR2 p.Ala128Thr Uncertain significance ★ ⚠ same type
AAR2 p.Ala235Thr Uncertain significance ★ ⚠ same type
AAR2 p.Ala371Asp Uncertain significance ★ ⚠ same type
AAR2 p.Ala371Val Uncertain significance ★ ⚠ same type
AAR2 p.Arg13His Uncertain significance ★ ⚠ same type
AAR2 p.Arg173His 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/aar2-p-val174met (accessed [today's date]).

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