Is CHN2 p.Arg404Trp (c.1210C>T) pathogenic?

CHN2 p.Arg404Trp (c.1210C>T) is classified Uncertain significance in CHN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). AlphaMissense: likely pathogenic (0.7818); Ultra-rare (popmax 0.02%, afr).

How common is CHN2 p.Arg404Trp (c.1210C>T) in the general population?

CHN2 p.Arg404Trp (c.1210C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about CHN2 p.Arg404Trp (c.1210C>T)?

AlphaMissense predicts likely pathogenic (score 0.7818) — an in-silico prediction, not a clinical call.

CHN2 p.Arg404Trp

c.1210C>T · rs142788210 · VCV3144481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7818	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -14.62	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.5	GERP -0.17, phastCons 0.99
Regional constraint	o/e 0.85	unconstrained · MANE · 318 kb · p 0.0002 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 0.02% African / African-American · 15/74,926 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00279% 45/1,613,730 alleles · ultra-rare exomes 34/1,461,522 · genomes 11/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,995
East Asian	0.00669%	14,958
South Asian	0.00329%	30,357
European (non-Finnish)	0.00195%	51,295
Finnishnot grpmax-eligible	0.00156%	64,010

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.Arg404Trp
Coding: c.1210C>T
MANE Select: NM_004067
dbSNP: rs142788210
Type: single nucleotide variant
Location: chr7:29509381 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.06 · 1 PDB
Residue 404: the rho-gap domain; an α-helix

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

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.Arg47Gln Uncertain significance ★ ⚠ same type
CHN2 p.Arg87Gln 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-arg404trp (accessed [today's date]).

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