Is CHN1 p.Arg73Trp (c.217C>T) pathogenic?

CHN1 p.Arg73Trp (c.217C>T) is classified Uncertain significance in CHN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely pathogenic (0.9926); Very rare (popmax 0.00161%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHN1 p.Arg73Trp (c.217C>T)?

CHN1 p.Arg73Trp (c.217C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHN1 p.Arg73Trp (c.217C>T) in the general population?

CHN1 p.Arg73Trp (c.217C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CHN1 p.Arg73Trp (c.217C>T)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

CHN1 p.Arg73Trp

c.217C>T · VCV3267080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -12.72	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 127 kb · p 0.27 · regional, not allelic
Overall
CADD	32.0	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 0.00161% European (non-Finnish) · 19/1,178,966 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00143% 23/1,611,508 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,794
European (non-Finnish)grpmax	0.00161%	62,051
African / African-American	0.00134%	74,776

Remaining individuals 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: CHN1
Protein: p.Arg73Trp
Coding: c.217C>T
MANE Select: NM_001822
Type: single nucleotide variant
Location: chr2:174915101 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 73: the sh2 domain; a β-strand

Full CHN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHN1 p.Ala27Gly Uncertain significance ★★ ⚠ same condition
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CHN1 p.Arg295Ile Uncertain significance ★ same condition
CHN1 p.Arg321Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CHN1 p.Arg428Lys Uncertain significance ★ ⚠ same condition
CHN1 p.Asn207Ser Uncertain significance ★ ⚠ same condition
CHN1 p.Asn337Thr Uncertain significance ★ ⚠ same condition
CHN1 p.Asp100Gly Uncertain significance ★ ⚠ same condition

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/chn1-p-arg73trp (accessed [today's date]).

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