Is RAB27A p.Pro58Ser (c.172C>T) pathogenic?

RAB27A p.Pro58Ser (c.172C>T) is classified Uncertain significance in RAB27A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0495%, mid); Associated with autoinflammatory syndrome.

What condition is associated with RAB27A p.Pro58Ser (c.172C>T)?

RAB27A p.Pro58Ser (c.172C>T) is associated with autoinflammatory syndrome, Griscelli syndrome type 2 (ClinVar).

How common is RAB27A p.Pro58Ser (c.172C>T) in the general population?

RAB27A p.Pro58Ser (c.172C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about RAB27A p.Pro58Ser (c.172C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

RAB27A p.Pro58Ser

c.172C>T · rs201284258 · VCV970666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -8.27	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 12	GERP 7.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 29 kb · p 0.53 · regional, not allelic
Overall
CADD	22.3	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 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0144% 232/1,613,418 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,228
European (non-Finnish)	0.0178%	5,617
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00533%	18,754
Admixed American	0.00167%	59,988

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.Pro58Ser
Coding: c.172C>T
MANE Select: NM_183235
dbSNP: rs201284258
Type: single nucleotide variant
Location: chr15:55230468 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.69 · 11 PDB
Residue 58: an α-helix

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

Disease context

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

Also linked: Griscelli syndrome type 2

Similar variants

RAB27A p.Pro58= Likely benign ★ same residue
RAB27A p.Pro58Gln Uncertain significance ★ ⚠ 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

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-pro58ser (accessed [today's date]).

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