Is RABL6 p.Arg690Pro (c.2069G>C) pathogenic?

RABL6 p.Arg690Pro (c.2069G>C) is classified Uncertain significance in RABL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.125); Very rare (popmax 0.00588%, amr).

How common is RABL6 p.Arg690Pro (c.2069G>C) in the general population?

RABL6 p.Arg690Pro (c.2069G>C) is very rare (popmax 0.00588%, amr) (gnomAD).

What do computational predictors say about RABL6 p.Arg690Pro (c.2069G>C)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

RABL6 p.Arg690Pro

c.2069G>C · VCV4575174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00588%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.07	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 0.55	GERP -1.7, phastCons 0.003
Regional constraint	o/e 1.26	unconstrained · MANE · 2,621 bp · p 1.7e-08 · regional, not allelic
Overall
CADD	8.501	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 0.00588% Admixed American · 3/51,024 alleles

Filtering AF 0.00156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.000967% 15/1,551,026 alleles · very rare exomes 12/1,398,896 · genomes 3/152,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00588%	17,008
Remaining individualsnot grpmax-eligible	0.00166%	60,162
African / African-American	0.00137%	73,056
European (non-Finnish)	0.000872%	114,743

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: RABL6
Protein: p.Arg690Pro
Coding: c.2069G>C
MANE Select: NM_024718
Type: single nucleotide variant
Location: chr9:136840401 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 60.84
Residue 690: the 'disordered' region; the 'interaction with cdkn2a' region

Full RABL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RABL6 p.Arg690Gln Uncertain significance ★★ ⚠ same residue
RABL6 p.Ser402Thr Uncertain significance ★★ ⚠ same type
RABL6 p.Ser535Gly Uncertain significance ★★ ⚠ same type
RABL6 p.Arg280His Benign/Likely benign ★★ same type
RABL6 p.Arg533His Benign ★★ same type
RABL6 p.Pro518Leu Benign ★★ same type
RABL6 p.Pro539= Benign ★★ same type
RABL6 p.Pro557= Benign/Likely benign ★★ 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/rabl6-p-arg690pro (accessed [today's date]).

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