Is GNB3 p.Ser67Phe (c.200C>T) pathogenic?

GNB3 p.Ser67Phe (c.200C>T) is classified Uncertain significance in GNB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-28). AlphaMissense: likely pathogenic (0.8867); Very rare (popmax 0.00213%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with GNB3 p.Ser67Phe (c.200C>T)?

GNB3 p.Ser67Phe (c.200C>T) is associated with inherited retinal dystrophy, congenital stationary night blindness 1H (ClinVar).

How common is GNB3 p.Ser67Phe (c.200C>T) in the general population?

GNB3 p.Ser67Phe (c.200C>T) is very rare (popmax 0.00213%, nfe) (gnomAD).

What do computational predictors say about GNB3 p.Ser67Phe (c.200C>T)?

AlphaMissense predicts likely pathogenic (score 0.8867) — an in-silico prediction, not a clinical call.

GNB3 p.Ser67Phe

c.200C>T · rs140263599 · VCV242986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00213%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.8867	likely pathogenic
REVEL	0.255	benign-leaning
SaProt	LLR -14.66	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,607 bp · p 0.03 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00213% European (non-Finnish) · 25/1,171,224 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00175% 28/1,602,794 alleles · very rare exomes 27/1,450,562 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00323%	30,973
European (non-Finnish)grpmax	0.00213%	46,849
Admixed American	0.00167%	59,758

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: GNB3
Protein: p.Ser67Phe
Coding: c.200C>T
MANE Select: NM_002075
dbSNP: rs140263599
Type: single nucleotide variant
Location: chr12:6843073 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.19 · 2 PDB
Residue 67: a UniProt-annotated variant site (in csnb1h; uncertain significance)

Full GNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital stationary night blindness 1H

Similar variants

GNB3 p.Lys57del Pathogenic same condition
GNB3 c.203+6G>A Uncertain significance ★★ same type
GNB3 p.Ala106Ser Uncertain significance ★★ ⚠ same type
GNB3 p.Ala231Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Ala64Thr Uncertain significance ★★ ⚠ same type
GNB3 p.Arg129His Uncertain significance ★★ ⚠ same type
GNB3 p.Arg137Gln Uncertain significance ★★ ⚠ same type
GNB3 p.Arg150Cys 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/gnb3-p-ser67phe (accessed [today's date]).

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