Is GNB1 p.Asp154= (c.462C>T) pathogenic?

GNB1 p.Asp154= (c.462C>T) is classified Benign/Likely benign in GNB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability, autosomal dominant 42.

What condition is associated with GNB1 p.Asp154= (c.462C>T)?

GNB1 p.Asp154= (c.462C>T) is associated with intellectual disability, autosomal dominant 42, acute lymphoblastic leukemia, myelodysplastic syndrome (ClinVar).

GNB1 p.Asp154=

Q: How common is GNB1 p.Asp154= (c.462C>T) in the general population?

GNB1 p.Asp154= (c.462C>T) is common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.462C>T · rs77027087 · VCV775489

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.48%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual disability, autosomal dominant 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.054	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.6, phastCons 1
Overall
CADD	13.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.48% African / African-American · 4,112/74,990 alleles

Filtering AF 5.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.29%

Overall 0.293% 4,733/1,613,392 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.48%	18
Remaining individualsnot grpmax-eligible	0.426%	235
Admixed American	0.41%	244
Middle Eastern	0.265%	378
South Asian	0.0132%	7,582
European (non-Finnish)	0.00687%	14,562

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.Asp154=
Coding: c.462C>T
MANE Select: NM_002074
dbSNP: rs77027087
Type: single nucleotide variant
Location: chr1:1793280 (GRCh38)
Gene constraint: LOEUF 0.222 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 97.04 · 1043 PDB

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

Disease context

intellectual disability, autosomal dominant 42 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute lymphoblastic leukemia myelodysplastic syndrome

Similar variants

GNB1 c.498-2A>G Likely pathogenic ★★ same condition
GNB1 p.Ala73Ser Pathogenic/Likely pathogenic ★★ same condition
GNB1 p.Ala73Thr Pathogenic/Likely pathogenic ★★ same condition
GNB1 p.Ala92Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
GNB1 p.Asp118Gly Pathogenic ★★ same condition
GNB1 p.Asp118His Likely pathogenic ★★ same condition
GNB1 p.Asp118Tyr Pathogenic ★★ same condition
GNB1 p.Asp76Asn Pathogenic/Likely pathogenic ★★ 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/gnb1-p-asp154 (accessed [today's date]).

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