Is RIGI p.Ser398Pro (c.1192T>C) pathogenic?

RIGI p.Ser398Pro (c.1192T>C) is classified Uncertain significance in RIGI (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-19). AlphaMissense: likely benign (0.0745); Ultra-rare (popmax 0.0165%, mid).

How common is RIGI p.Ser398Pro (c.1192T>C) in the general population?

RIGI p.Ser398Pro (c.1192T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about RIGI p.Ser398Pro (c.1192T>C)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

RIGI p.Ser398Pro

c.1192T>C · rs1447906391 · VCV1362467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.3, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,762 bp · p 2.3e-06 · regional, not allelic
Overall
CADD	19.82	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000124% 2/1,614,052 alleles · ultra-rare exomes 2/1,461,800 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00167%	60,014

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.Ser398Pro
Coding: c.1192T>C
MANE Select: NM_014314
dbSNP: rs1447906391
Type: single nucleotide variant
Location: chr9:32487965 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 398: a β-strand; the helicase atp-binding 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-ser398pro (accessed [today's date]).

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