Is RABL6 p.Pro409Ser (c.1225C>T) pathogenic?

RABL6 p.Pro409Ser (c.1225C>T) is classified Uncertain significance in RABL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0258%, afr).

How common is RABL6 p.Pro409Ser (c.1225C>T) in the general population?

RABL6 p.Pro409Ser (c.1225C>T) is ultra-rare (popmax 0.0258%, afr) (gnomAD).

What do computational predictors say about RABL6 p.Pro409Ser (c.1225C>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

RABL6 p.Pro409Ser

c.1225C>T · rs765209775 · VCV2290107

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0258%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.12	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 0.38	GERP -0.18
Regional constraint	o/e 1.26	unconstrained · MANE · 2,621 bp · p 1.7e-08 · regional, not allelic
Overall
CADD	16.22	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 0.0258% African / African-American · 19/73,722 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.00159% 25/1,567,966 alleles · ultra-rare exomes 14/1,415,734 · genomes 11/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0258%	3,880
Admixed American	0.00376%	26,602
Remaining individualsnot grpmax-eligible	0.00329%	30,392
European (non-Finnish)	0.000173%	578,647

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.Pro409Ser
Coding: c.1225C>T
MANE Select: NM_024718
dbSNP: rs765209775
Type: single nucleotide variant
Location: chr9:136837960 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 60.84
Residue 409: the 'disordered' region

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

Similar variants

RABL6 p.Arg690Gln Uncertain significance ★★ ⚠ same type
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-pro409ser (accessed [today's date]).

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