Is CHN2 p.His124Arg (c.371A>G) pathogenic?

CHN2 p.His124Arg (c.371A>G) is classified Uncertain significance in CHN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.7778); Absent from gnomAD v4.1.

How common is CHN2 p.His124Arg (c.371A>G) in the general population?

CHN2 p.His124Arg (c.371A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHN2 p.His124Arg (c.371A>G)?

AlphaMissense predicts likely pathogenic (score 0.7778) — an in-silico prediction, not a clinical call.

CHN2 p.His124Arg

c.371A>G · VCV4002476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7778 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7778	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	LLR -11.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 318 kb · p 0.0002 · regional, not allelic
Overall
CADD	26.1	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

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: CHN2
Protein: p.His124Arg
Coding: c.371A>G
MANE Select: NM_004067
Type: single nucleotide variant
Location: chr7:29400623 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.06 · 1 PDB
Residue 124: the sh2 domain

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.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-his124arg (accessed [today's date]).

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