Is ARCN1 p.Ala217Pro (c.649G>C) pathogenic?

ARCN1 p.Ala217Pro (c.649G>C) is classified Uncertain significance in ARCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-19). AlphaMissense: likely benign (0.1018); Absent from gnomAD v4.1; Associated with ARCN1-related disorder.

What condition is associated with ARCN1 p.Ala217Pro (c.649G>C)?

ARCN1 p.Ala217Pro (c.649G>C) is associated with ARCN1-related disorder (ClinVar).

How common is ARCN1 p.Ala217Pro (c.649G>C) in the general population?

ARCN1 p.Ala217Pro (c.649G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARCN1 p.Ala217Pro (c.649G>C)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

ARCN1 p.Ala217Pro

c.649G>C · rs2497685677 · VCV2629888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ARCN1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.47	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 2.5	GERP 0.73, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 17 kb · p 0.00011 · regional, not allelic
Overall
CADD	17.17	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

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: ARCN1
Protein: p.Ala217Pro
Coding: c.649G>C
MANE Select: NM_001655
dbSNP: rs2497685677
Type: single nucleotide variant
Location: chr11:118584010 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.25

Full ARCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ARCN1-related disorder

Similar variants

ARCN1 p.Arg435Ter Pathogenic/Likely pathogenic ★★ same condition
ARCN1 c.984+7A>G Likely benign same condition
ARCN1 p.Arg171fs Pathogenic ★ same condition
ARCN1 p.Lys347fs Likely pathogenic ★ same condition
ARCN1 p.Val325fs Likely pathogenic ★ same condition
ARCN1 c.654-15A>G Pathogenic/Likely pathogenic ★★ same type
ARCN1 p.Arg170Ter Pathogenic ★★ same type
ARCN1 p.Arg312Ter Pathogenic ★★ 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/arcn1-p-ala217pro (accessed [today's date]).

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