Is AAR2 p.Ala371Val (c.1112C>T) pathogenic?

AAR2 p.Ala371Val (c.1112C>T) is classified Uncertain significance in AAR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.253); Rare (popmax 0.122%, sas).

How common is AAR2 p.Ala371Val (c.1112C>T) in the general population?

AAR2 p.Ala371Val (c.1112C>T) is rare (popmax 0.122%, sas) (gnomAD).

What do computational predictors say about AAR2 p.Ala371Val (c.1112C>T)?

AlphaMissense predicts likely benign (score 0.253) — an in-silico prediction, not a clinical call.

AAR2 p.Ala371Val

c.1112C>T · rs201095536 · VCV2350251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.253 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.253	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 16 kb · p 0.0057 · regional, not allelic
Overall
CADD	25.8	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 0.122% South Asian · 111/91,074 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0965%

Overall 0.0172% 277/1,614,144 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.125%	800
South Asiangrpmax	0.122%	820
Middle Eastern	0.033%	3,030
Finnishnot grpmax-eligible	0.0219%	4,573
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.01%	10,003
European (non-Finnish)	0.00788%	12,688
African / African-American	0.00133%	75,034

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala371Val
Coding: c.1112C>T
MANE Select: NM_001271874
dbSNP: rs201095536
Type: single nucleotide variant
Location: chr20:36255702 (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

Similar variants

AAR2 p.Ala371Asp 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.Arg13His Uncertain significance ★ ⚠ same type
AAR2 p.Arg173His Uncertain significance ★ ⚠ same type
AAR2 p.Arg180Cys Uncertain significance ★ ⚠ same type
AAR2 p.Arg180His 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-ala371val (accessed [today's date]).

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