Is RAB27A p.Pro158Arg (c.473C>G) pathogenic?

RAB27A p.Pro158Arg (c.473C>G) is classified Uncertain significance in RAB27A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely benign (0.2911); Very rare (popmax 0.00549%, sas); Associated with Griscelli syndrome type 2.

What condition is associated with RAB27A p.Pro158Arg (c.473C>G)?

RAB27A p.Pro158Arg (c.473C>G) is associated with Griscelli syndrome type 2 (ClinVar).

How common is RAB27A p.Pro158Arg (c.473C>G) in the general population?

RAB27A p.Pro158Arg (c.473C>G) is very rare (popmax 0.00549%, sas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RAB27A p.Pro158Arg (c.473C>G)?

AlphaMissense predicts likely benign (score 0.2911) — an in-silico prediction, not a clinical call.

RAB27A p.Pro158Arg

c.473C>G · rs746081723 · VCV851791

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Griscelli syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.2911	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 29 kb · p 0.53 · regional, not allelic
Overall
CADD	25.0	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 0.00549% South Asian · 5/91,058 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000496% 8/1,613,364 alleles · very rare exomes 8/1,461,136 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,212
East Asian	0.00446%	22,431
European (non-Finnish)	8.48e-05%	1,179,359

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: RAB27A
Protein: p.Pro158Arg
Coding: c.473C>G
MANE Select: NM_183235
dbSNP: rs746081723
Type: single nucleotide variant
Location: chr15:55205700 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.69 · 11 PDB

Full RAB27A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Griscelli syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

RAB27A p.Pro158= Likely benign ★ same residue
RAB27A c.239+1G>T Pathogenic ★★ same condition
RAB27A c.467+1G>C Pathogenic/Likely pathogenic ★★ same condition
RAB27A p.Ala76Val Pathogenic/Likely pathogenic ★★ same condition
RAB27A p.Arg184Ter Pathogenic ★★ same condition
RAB27A p.Arg82Cys Pathogenic/Likely pathogenic ★★ same condition
RAB27A p.Asp74His Likely pathogenic ★★ same condition
RAB27A p.Gln118Ter Pathogenic ★★ 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/rab27a-p-pro158arg (accessed [today's date]).

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