Is RABL3 p.Phe84Ser (c.251T>C) pathogenic?

RABL3 p.Phe84Ser (c.251T>C) is classified Uncertain significance in RABL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.00849%, nfe).

How common is RABL3 p.Phe84Ser (c.251T>C) in the general population?

RABL3 p.Phe84Ser (c.251T>C) is very rare (popmax 0.00849%, nfe) (gnomAD).

What do computational predictors say about RABL3 p.Phe84Ser (c.251T>C)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

RABL3 p.Phe84Ser

c.251T>C · rs748467485 · VCV2350388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00849%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic · top 7% in RABL3
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 53 kb · p 0.32 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00849% European (non-Finnish) · 100/1,178,238 alleles

Filtering AF 0.00709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00645% 104/1,611,284 alleles · very rare exomes 95/1,459,196 · genomes 9/152,088 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00849%	11,782
Finnishnot grpmax-eligible	0.00312%	32,003
Remaining individualsnot grpmax-eligible	0.0016%	62,388
African / African-American	0.00134%	74,800

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: RABL3
Protein: p.Phe84Ser
Coding: c.251T>C
MANE Select: NM_173825
dbSNP: rs748467485
Type: single nucleotide variant
Location: chr3:120709797 (GRCh38)
Gene constraint: LOEUF 1.415 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 81.14
Residue 84: the 'small gtpase-like' region; a UniProt-annotated variant site (in pnca5; associated with disease susceptibility; increased kras signaling and cell proliferation; increased interaction with rap1gds1; increased kras prenylation); the 'switch-ii' region

Full RABL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RABL3 p.His95= Likely benign ★★ same type
RABL3 p.Arg222Gly Uncertain significance ★ same type
RABL3 p.Asn127Tyr Uncertain significance ★ ⚠ same type
RABL3 p.Asn172Ser Uncertain significance ★ ⚠ same type
RABL3 p.Asn192Lys Uncertain significance ★ ⚠ same type
RABL3 p.Cys180Gly Uncertain significance ★ ⚠ same type
RABL3 p.Cys27Phe Uncertain significance ★ ⚠ same type
RABL3 p.Gly128Glu 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/rabl3-p-phe84ser (accessed [today's date]).

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