Is RIGI p.Ala684Val (c.2051C>T) pathogenic?

RIGI p.Ala684Val (c.2051C>T) is classified Uncertain significance in RIGI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-24). AlphaMissense: likely benign (0.1261); Very rare (popmax 0.000255%, nfe).

How common is RIGI p.Ala684Val (c.2051C>T) in the general population?

RIGI p.Ala684Val (c.2051C>T) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about RIGI p.Ala684Val (c.2051C>T)?

AlphaMissense predicts likely benign (score 0.1261) — an in-silico prediction, not a clinical call.

RIGI p.Ala684Val

c.2051C>T · rs2489295995 · VCV2058428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1261	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 2.1, phastCons 0.54
Regional constraint	o/e 1.05	unconstrained · MANE · 12 kb · p 0.59 · regional, not allelic
Overall
CADD	19.44	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,654 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,326 alleles · very rare exomes 3/1,459,992 · genomes 0/152,334 · joint denominator

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.Ala684Val
Coding: c.2051C>T
MANE Select: NM_014314
dbSNP: rs2489295995
Type: single nucleotide variant
Location: chr9:32467896 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 684: 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-ala684val (accessed [today's date]).

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