Is ARR3 p.Arg61Cys (c.181C>T) pathogenic?

ARR3 p.Arg61Cys (c.181C>T) is classified Conflicting classifications of pathogenicity in ARR3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1227); Very rare (popmax 0.00704%, sas); Associated with Inborn genetic diseases.

What condition is associated with ARR3 p.Arg61Cys (c.181C>T)?

ARR3 p.Arg61Cys (c.181C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ARR3 p.Arg61Cys (c.181C>T) in the general population?

ARR3 p.Arg61Cys (c.181C>T) is very rare (popmax 0.00704%, sas) (gnomAD).

What do computational predictors say about ARR3 p.Arg61Cys (c.181C>T)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

ARR3 p.Arg61Cys

c.181C>T · VCV4148498

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00704%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.34	GERP 2.2
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	23.6	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 0.00704% South Asian · 4/56,827 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00141%

Overall 0.00174% 21/1,210,115 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00704%	14,207
Remaining individualsnot grpmax-eligible	0.0042%	23,798
European (non-Finnish)	0.00168%	59,685

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.Arg61Cys
Coding: c.181C>T
MANE Select: NM_004312
Type: single nucleotide variant
Location: chrX:70276117 (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.Arg61Leu 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-arg61cys (accessed [today's date]).

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