Is RIGI p.Asp421Ala (c.1262A>C) pathogenic?

RIGI p.Asp421Ala (c.1262A>C) is classified Uncertain significance in RIGI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-27). AlphaMissense: likely benign (0.0669); Very rare (popmax 0.00542%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RIGI p.Asp421Ala (c.1262A>C)?

RIGI p.Asp421Ala (c.1262A>C) is associated with Inborn genetic diseases (ClinVar).

How common is RIGI p.Asp421Ala (c.1262A>C) in the general population?

RIGI p.Asp421Ala (c.1262A>C) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about RIGI p.Asp421Ala (c.1262A>C)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

RIGI p.Asp421Ala

c.1262A>C · rs761902508 · VCV1509462

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.9
Regional constraint	o/e 1.10	unconstrained · MANE · 2,408 bp · p 0.37 · regional, not allelic
Overall
CADD	7.538	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 0.00542% European (non-Finnish) · 64/1,180,018 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00397% 64/1,614,056 alleles · very rare exomes 61/1,461,868 · genomes 3/152,188 · 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.Asp421Ala
Coding: c.1262A>C
MANE Select: NM_014314
dbSNP: rs761902508
Type: single nucleotide variant
Location: chr9:32487584 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 421: an α-helix; the helicase atp-binding domain; the 'interaction with zc3hav1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIGI p.Asp421Val Uncertain significance ★ ⚠ same residue
RIGI p.Ala436Val Uncertain significance ★★ ⚠ same condition
RIGI p.Ala537Ser Uncertain significance ★★ ⚠ same condition
RIGI p.Ala537Thr Uncertain significance ★★ ⚠ same condition
RIGI p.Ala774Thr Uncertain significance ★★ ⚠ same condition
RIGI p.Arg109Cys Uncertain significance ★★ ⚠ same condition
RIGI p.Arg34Gly Uncertain significance ★★ ⚠ same condition
RIGI p.Arg664His Uncertain significance ★★ ⚠ same condition

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-asp421ala (accessed [today's date]).

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