Is ARR3 p.Leu44Phe (c.132A>C) pathogenic?

ARR3 p.Leu44Phe (c.132A>C) is classified Uncertain significance in ARR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1996); Ultra-rare (popmax 0.015%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARR3 p.Leu44Phe (c.132A>C)?

ARR3 p.Leu44Phe (c.132A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ARR3 p.Leu44Phe (c.132A>C) in the general population?

ARR3 p.Leu44Phe (c.132A>C) is ultra-rare (popmax 0.015%, nfe) (gnomAD).

What do computational predictors say about ARR3 p.Leu44Phe (c.132A>C)?

AlphaMissense predicts likely benign (score 0.1996) — an in-silico prediction, not a clinical call.

ARR3 p.Leu44Phe

c.132A>C · rs11548182 · VCV2460360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1996	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.80	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 3	GERP -3.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 0.01 · regional, not allelic
Overall
CADD	17.99	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 0.015% European (non-Finnish) · 134/894,372 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0122% 148/1,209,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0231%	4,326
European (non-Finnish)grpmax	0.015%	6,674
African / African-American	0.00524%	19,093

Remaining individuals 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: ARR3
Protein: p.Leu44Phe
Coding: c.132A>C
MANE Select: NM_004312
dbSNP: rs11548182
Type: single nucleotide variant
Location: chrX:70270131 (GRCh38)
Structure: AlphaFold pLDDT 87.37
Residue 44: a UniProt-annotated variant site (in)

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-leu44phe (accessed [today's date]).

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