Is ARR3 p.Pro345Ser (c.1033C>T) pathogenic?

ARR3 p.Pro345Ser (c.1033C>T) is classified Uncertain significance in ARR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.3852); Very rare (popmax 0.00592%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARR3 p.Pro345Ser (c.1033C>T)?

ARR3 p.Pro345Ser (c.1033C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ARR3 p.Pro345Ser (c.1033C>T) in the general population?

ARR3 p.Pro345Ser (c.1033C>T) is very rare (popmax 0.00592%, nfe) (gnomAD).

What do computational predictors say about ARR3 p.Pro345Ser (c.1033C>T)?

AlphaMissense predicts ambiguous (score 0.3852) — an in-silico prediction, not a clinical call.

ARR3 p.Pro345Ser

c.1033C>T · VCV3948802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00592%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3852	ambiguous
REVEL	0.567	indeterminate
SaProt	LLR -11.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	22.5	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 0.00592% European (non-Finnish) · 53/895,068 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00419%

Overall 0.00455% 55/1,209,272 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00592%	16,888
South Asian	0.00176%	56,747
African / African-American	0.00176%	56,844

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.Pro345Ser
Coding: c.1033C>T
MANE Select: NM_004312
Type: single nucleotide variant
Location: chrX:70280785 (GRCh38)
Structure: AlphaFold pLDDT 87.37
Residue 345: a UniProt-annotated variant site (in myp26; uncertain significance)

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.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
ARR3 p.Arg186His 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-pro345ser (accessed [today's date]).

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