Is ARRDC3 p.Pro346Leu (c.1037C>T) pathogenic?

ARRDC3 p.Pro346Leu (c.1037C>T) is classified Uncertain significance in ARRDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). AlphaMissense: likely pathogenic (0.8398); Absent from gnomAD v4.1.

How common is ARRDC3 p.Pro346Leu (c.1037C>T) in the general population?

ARRDC3 p.Pro346Leu (c.1037C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARRDC3 p.Pro346Leu (c.1037C>T)?

AlphaMissense predicts likely pathogenic (score 0.8398) — an in-silico prediction, not a clinical call.

ARRDC3 p.Pro346Leu

c.1037C>T · rs2530868696 · VCV3129858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8398 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8398	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -11.21	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 4.7e-08 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARRDC3
Protein: p.Pro346Leu
Coding: c.1037C>T
MANE Select: NM_020801
dbSNP: rs2530868696
Type: single nucleotide variant
Location: chr5:91373835 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.36 · 3 PDB
Residue 346: an α-helix

Full ARRDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRDC3 p.Ala227Thr Uncertain significance ★ ⚠ same type
ARRDC3 p.Ala65Thr Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg109Gly Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg135His Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg284His Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg414Cys Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg414His Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg43Ser 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/arrdc3-p-pro346leu (accessed [today's date]).

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