Is GNB1 p.Phe199= (c.597C>T) pathogenic?

GNB1 p.Phe199= (c.597C>T) is classified Likely benign in GNB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0134%, afr).

How common is GNB1 p.Phe199= (c.597C>T) in the general population?

GNB1 p.Phe199= (c.597C>T) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

GNB1 p.Phe199=

c.597C>T · rs538188811 · VCV1669565

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.086	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.62	GERP -1.7, phastCons 0.88
Overall
CADD	12.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% African / African-American · 10/74,866 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00261% 42/1,611,872 alleles · ultra-rare exomes 39/1,459,780 · genomes 3/152,092 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,241
African / African-Americangrpmax	0.0134%	7,487
Finnishnot grpmax-eligible	0.00312%	32,012
East Asian	0.00223%	44,876
South Asian	0.0022%	45,510
European (non-Finnish)	0.00144%	69,302

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: GNB1
Protein: p.Phe199=
Coding: c.597C>T
MANE Select: NM_002074
dbSNP: rs538188811
Type: single nucleotide variant
Location: chr1:1790497 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 97.04 · 1043 PDB
Residue 199: a β-strand

Full GNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNB1 c.498-2A>G Likely pathogenic ★★ same type
GNB1 p.Ala73Ser Pathogenic/Likely pathogenic ★★ same type
GNB1 p.Ala73Thr Pathogenic/Likely pathogenic ★★ same type
GNB1 p.Ala92Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
GNB1 p.Asp118Gly Pathogenic ★★ same type
GNB1 p.Asp118His Likely pathogenic ★★ same type
GNB1 p.Asp118Tyr Pathogenic ★★ same type
GNB1 p.Asp76Asn Pathogenic/Likely pathogenic ★★ 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/gnb1-p-phe199 (accessed [today's date]).

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