Is RIGI p.Leu643= (c.1927T>C) pathogenic?

RIGI p.Leu643= (c.1927T>C) is classified Likely benign in RIGI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). Ultra-rare (popmax 0.0138%, amr).

How common is RIGI p.Leu643= (c.1927T>C) in the general population?

RIGI p.Leu643= (c.1927T>C) is ultra-rare (popmax 0.0138%, amr) (gnomAD).

RIGI p.Leu643=

c.1927T>C · rs143746778 · VCV1899630

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, amr)

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 5.5	GERP 0.92, phastCons 1
Overall
CADD	8.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0138% Admixed American · 8/58,056 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00496%

Overall 0.000562% 9/1,601,212 alleles · ultra-rare exomes 9/1,448,958 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0138%	7,257
Remaining individualsnot grpmax-eligible	0.00161%	61,996

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.Leu643=
Coding: c.1927T>C
MANE Select: NM_014314
dbSNP: rs143746778
Type: single nucleotide variant
Location: chr9:32473062 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 643: an α-helix; the helicase c-terminal domain; 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-leu643 (accessed [today's date]).

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