Is ARCN1 p.Ile422= (c.1266C>T) pathogenic?

ARCN1 p.Ile422= (c.1266C>T) is classified Benign in ARCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). Very rare (popmax 0.00769%, sas).

How common is ARCN1 p.Ile422= (c.1266C>T) in the general population?

ARCN1 p.Ile422= (c.1266C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

ARCN1 p.Ile422=

c.1266C>T · rs181814063 · VCV2072997

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -0.76, phastCons 0.82
Overall
CADD	12.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00769% South Asian · 7/91,074 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00929% 150/1,614,152 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0734%	1,362
Remaining individualsnot grpmax-eligible	0.0256%	3,907
South Asiangrpmax	0.00769%	13,011
European (non-Finnish)	0.00653%	15,325
African / African-American	0.00267%	37,519
Admixed American	0.00167%	60,024

Finnish 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: ARCN1
Protein: p.Ile422=
Coding: c.1266C>T
MANE Select: NM_001655
dbSNP: rs181814063
Type: single nucleotide variant
Location: chr11:118597731 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.25
Residue 422: the mhd domain

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

Similar variants

ARCN1 p.Ile422Val Uncertain significance ★ ⚠ same residue
ARCN1 c.654-15A>G Pathogenic/Likely pathogenic ★★ same type
ARCN1 p.Arg170Ter Pathogenic ★★ same type
ARCN1 p.Arg312Ter Pathogenic ★★ same type
ARCN1 p.Arg435Ter Pathogenic/Likely pathogenic ★★ same type
ARCN1 p.Ala169Val Uncertain significance ★★ ⚠ same type
ARCN1 p.Arg160His Uncertain significance ★★ ⚠ same type
ARCN1 p.Arg161His 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/arcn1-p-ile422 (accessed [today's date]).

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