Is CGN p.Arg227Trp (c.679C>T) pathogenic?

CGN p.Arg227Trp (c.679C>T) is classified Likely benign in CGN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-28). Rare (popmax 0.159%, nfe).

How common is CGN p.Arg227Trp (c.679C>T) in the general population?

CGN p.Arg227Trp (c.679C>T) is rare (popmax 0.159%, nfe) (gnomAD).

CGN p.Arg227Trp

c.679C>T · rs140625740 · VCV737275

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.159%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.267	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1.8, phastCons 0.78
Regional constraint	o/e 0.97	unconstrained · MANE · 16 kb · p 0.38 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.159% European (non-Finnish) · 1,878/1,180,044 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.149% 2,401/1,614,082 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.474%	211
European (non-Finnish)grpmax	0.159%	628
South Asian	0.122%	821
Remaining individualsnot grpmax-eligible	0.106%	947
Middle Eastern	0.0495%	2,021
African / African-American	0.0346%	2,887
Admixed American	0.015%	6,670
East Asian	0.0111%	8,978

Finnish 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: CGN
Protein: p.Arg227Trp
Coding: c.679C>T
MANE Select: NM_020770
dbSNP: rs140625740
Type: single nucleotide variant
Location: chr1:151519198 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.44
Residue 227: the 'head' region; the 'disordered' region

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

Similar variants

CGN p.Ala357= Benign/Likely benign ★★ same type
CGN p.Arg11Trp Likely benign ★★ same type
CGN p.Arg547Lys Benign ★★ same type
CGN p.Arg973Gln Benign ★★ same type
CGN p.Glu771Lys Benign/Likely benign ★★ same type
CGN p.Ile60= Benign ★★ same type
CGN p.Ala1035Thr Uncertain significance ★ same type
CGN p.Ala142Val 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/cgn-p-arg227trp (accessed [today's date]).

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