Is CHN2 p.Ile461Val (c.1381A>G) pathogenic?

CHN2 p.Ile461Val (c.1381A>G) is classified Uncertain significance in CHN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely benign (0.1678); Ultra-rare (popmax 0.033%, mid); Associated with neuropathy, congenital hypomyelinating, 2.

What condition is associated with CHN2 p.Ile461Val (c.1381A>G)?

CHN2 p.Ile461Val (c.1381A>G) is associated with neuropathy, congenital hypomyelinating, 2 (ClinVar).

How common is CHN2 p.Ile461Val (c.1381A>G) in the general population?

CHN2 p.Ile461Val (c.1381A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CHN2 p.Ile461Val (c.1381A>G)?

AlphaMissense predicts likely benign (score 0.1678) — an in-silico prediction, not a clinical call.

CHN2 p.Ile461Val

c.1381A>G · rs2487624745 · VCV3065517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, congenital hypomyelinating, 2

Computational evidence

Protein change
AlphaMissense	0.1678	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -9.91	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 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 318 kb · p 0.0002 · regional, not allelic
Overall
CADD	21.6	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000137% 2/1,461,844 alleles · ultra-rare

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: CHN2
Protein: p.Ile461Val
Coding: c.1381A>G
MANE Select: NM_004067
dbSNP: rs2487624745
Type: single nucleotide variant
Location: chr7:29512709 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.06 · 1 PDB
Residue 461: the rho-gap domain; an α-helix

Full CHN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuropathy, congenital hypomyelinating, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHN2 p.Ala201Val Uncertain significance ★ ⚠ same type
CHN2 p.Ala3Thr Uncertain significance ★ ⚠ same type
CHN2 p.Arg290Ser Uncertain significance ★ ⚠ same type
CHN2 p.Arg299Gln Uncertain significance ★ ⚠ same type
CHN2 p.Arg313Thr Uncertain significance ★ ⚠ same type
CHN2 p.Arg39His Uncertain significance ★ ⚠ same type
CHN2 p.Arg404Trp Uncertain significance ★ ⚠ same type
CHN2 p.Arg47Gln 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/chn2-p-ile461val (accessed [today's date]).

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