Is ARR3 p.Arg21Gln (c.62G>A) pathogenic?

ARR3 p.Arg21Gln (c.62G>A) is classified Uncertain significance in ARR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.6854); Very rare (popmax 0.00414%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARR3 p.Arg21Gln (c.62G>A)?

ARR3 p.Arg21Gln (c.62G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ARR3 p.Arg21Gln (c.62G>A) in the general population?

ARR3 p.Arg21Gln (c.62G>A) is very rare (popmax 0.00414%, nfe) (gnomAD).

What do computational predictors say about ARR3 p.Arg21Gln (c.62G>A)?

AlphaMissense predicts likely pathogenic (score 0.6854) — an in-silico prediction, not a clinical call.

ARR3 p.Arg21Gln

c.62G>A · VCV4585491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00414%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6854	likely pathogenic
REVEL	0.408	indeterminate
SaProt	LLR -11.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.3, phastCons 0.019
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00414% European (non-Finnish) · 37/894,081 alleles

Filtering AF 0.00305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00347% 38/1,095,232 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00414%	24,164
Finnishnot grpmax-eligible	0.00214%	46,699

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: ARR3
Protein: p.Arg21Gln
Coding: c.62G>A
MANE Select: NM_004312
Type: single nucleotide variant
Location: chrX:70269865 (GRCh38)
Structure: AlphaFold pLDDT 87.37

Full ARR3 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

ARR3 p.Arg21Trp Uncertain significance ★ ⚠ same residue
ARR3 p.Val82Met Uncertain significance ★★ ⚠ same condition
ARR3 p.Arg282Gln Likely benign ★★ ⚠ same condition
ARR3 p.Ala357Ser Uncertain significance ★ ⚠ same condition
ARR3 p.Arg166Gln Uncertain significance ★ ⚠ same condition
ARR3 p.Arg185Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
ARR3 p.Arg185Pro Uncertain significance ★ ⚠ same condition
ARR3 p.Arg186Cys Conflicting classifications of pathogenicity ★ ⚠ 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/arr3-p-arg21gln (accessed [today's date]).

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