Is RIGI p.Thr441= (c.1323A>G) pathogenic?

RIGI p.Thr441= (c.1323A>G) is classified Benign/Likely benign in RIGI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele.

RIGI p.Thr441=

Q: How common is RIGI p.Thr441= (c.1323A>G) in the general population?

RIGI p.Thr441= (c.1323A>G) is common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1323A>G · rs2274863 · VCV1169187

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -3.2, phastCons 0.005
Overall
CADD	3.922	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.7% East Asian · 6,611/44,880 alleles

Filtering AF 14.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.3%

Overall 1.53% 24,713/1,614,132 alleles · common exomes 17,883/1,461,864 · genomes 6,830/152,268 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	14.7%	7
African / African-American	12.1%	8
South Asian	3.63%	28
Admixed American	3.26%	31
Remaining individualsnot grpmax-eligible	2.35%	43
Middle Eastern	1.29%	78
Ashkenazi Jewishnot grpmax-eligible	0.996%	100
Finnishnot grpmax-eligible	0.584%	171
European (non-Finnish)	0.128%	779

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: RIGI
Protein: p.Thr441=
Coding: c.1323A>G
MANE Select: NM_014314
dbSNP: rs2274863
Type: single nucleotide variant
Location: chr9:32487523 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 441: the 'interaction with zc3hav1' region

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

Similar variants

RIGI c.1923+1G>A Uncertain significance ★★ same type
RIGI c.954-6T>G Uncertain significance ★★ same type
RIGI p.Ala436Val Uncertain significance ★★ ⚠ same type
RIGI p.Ala486Thr Uncertain significance ★★ ⚠ same type
RIGI p.Ala537Ser Uncertain significance ★★ ⚠ same type
RIGI p.Ala537Thr Uncertain significance ★★ ⚠ same type
RIGI p.Ala774Thr Uncertain significance ★★ ⚠ same type
RIGI p.Arg109Cys 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/rigi-p-thr441 (accessed [today's date]).

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