Is CGN p.Arg199His (c.596G>A) pathogenic?

CGN p.Arg199His (c.596G>A) is classified Uncertain significance in CGN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). Ultra-rare (popmax 0.0134%, eas).

How common is CGN p.Arg199His (c.596G>A) in the general population?

CGN p.Arg199His (c.596G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

CGN p.Arg199His

c.596G>A · rs375611149 · VCV3143932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.131	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 16 kb · p 0.38 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,896 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00341% 55/1,613,944 alleles · ultra-rare exomes 49/1,461,744 · genomes 6/152,200 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0624%	1,602
East Asiangrpmax	0.0134%	7,483
African / African-American	0.00267%	37,466
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000593%	168,577

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: CGN
Protein: p.Arg199His
Coding: c.596G>A
MANE Select: NM_020770
dbSNP: rs375611149
Type: single nucleotide variant
Location: chr1:151519115 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.44
Residue 199: the 'head' region; the 'disordered' region

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

Similar variants

CGN p.Arg199Cys Uncertain significance ★ same residue
CGN p.Ala357= Benign/Likely benign ★★ same type
CGN p.Arg11Trp Likely benign ★★ same type
CGN p.Arg227Trp 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

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-arg199his (accessed [today's date]).

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