Is GNAI3 p.Val136= (c.408A>T) pathogenic?

GNAI3 p.Val136= (c.408A>T) is classified Benign/Likely benign in GNAI3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-15). Ultra-rare (popmax 0.0122%, nfe).

How common is GNAI3 p.Val136= (c.408A>T) in the general population?

GNAI3 p.Val136= (c.408A>T) is ultra-rare (popmax 0.0122%, nfe) (gnomAD).

GNAI3 p.Val136=

c.408A>T · rs781178254 · VCV2170169

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP -1.1, phastCons 1
Overall
CADD	7.041	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% European (non-Finnish) · 143/1,173,482 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00987%

Overall 0.0111% 178/1,606,930 alleles · ultra-rare exomes 159/1,454,672 · genomes 19/152,258 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0422%	2,370
European (non-Finnish)grpmax	0.0122%	8,206
Remaining individualsnot grpmax-eligible	0.00963%	10,380
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,554
Admixed American	0.00167%	60,002

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: GNAI3
Protein: p.Val136=
Coding: c.408A>T
MANE Select: NM_006496
dbSNP: rs781178254
Type: single nucleotide variant
Location: chr1:109579308 (GRCh38)
Gene constraint: LOEUF 1.113 · pLI 0.17 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 27 PDB
Residue 136: the g-alpha domain; an α-helix

Full GNAI3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GNAI3 p.Gly40Arg Pathogenic/Likely pathogenic ★★ same type
GNAI3 p.Gly40Val Likely pathogenic ★★ same type
GNAI3 p.Ser47Asn Pathogenic/Likely pathogenic ★★ same type
GNAI3 p.Gly292Cys Uncertain significance ★★ ⚠ same type
GNAI3 p.Ile49Thr Uncertain significance ★★ ⚠ same type
GNAI3 p.Lys10Arg Uncertain significance ★★ ⚠ same type
GNAI3 p.Phe108Leu Uncertain significance ★★ ⚠ same type
GNAI3 c.591-18T>G 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/gnai3-p-val136 (accessed [today's date]).

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