Is ARCN1 p.Val274Ile (c.820G>A) pathogenic?

ARCN1 p.Val274Ile (c.820G>A) is classified Uncertain significance in ARCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0841); Very rare (popmax 0.00935%, afr).

How common is ARCN1 p.Val274Ile (c.820G>A) in the general population?

ARCN1 p.Val274Ile (c.820G>A) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about ARCN1 p.Val274Ile (c.820G>A)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

ARCN1 p.Val274Ile

c.820G>A · VCV4709326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -8.31	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 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 17 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.1	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 0.00935% African / African-American · 7/74,858 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000683% 11/1,611,318 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,694
Remaining individualsnot grpmax-eligible	0.0016%	62,406
South Asian	0.0011%	90,988
European (non-Finnish)	0.00017%	588,859

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.Val274Ile
Coding: c.820G>A
MANE Select: NM_001655
Type: single nucleotide variant
Location: chr11:118590342 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.25
Residue 274: the mhd domain

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

Similar variants

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
ARCN1 p.Arg314His 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-val274ile (accessed [today's date]).

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