Is RAB27A p.Ala92Val (c.275C>T) pathogenic?

RAB27A p.Ala92Val (c.275C>T) is classified Uncertain significance in RAB27A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-23). AlphaMissense: likely pathogenic (0.9229); Ultra-rare (popmax 0.0329%, mid); Associated with autoinflammatory syndrome.

What condition is associated with RAB27A p.Ala92Val (c.275C>T)?

RAB27A p.Ala92Val (c.275C>T) is associated with autoinflammatory syndrome, Griscelli syndrome type 2 (ClinVar).

How common is RAB27A p.Ala92Val (c.275C>T) in the general population?

RAB27A p.Ala92Val (c.275C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about RAB27A p.Ala92Val (c.275C>T)?

AlphaMissense predicts likely pathogenic (score 0.9229) — an in-silico prediction, not a clinical call.

RAB27A p.Ala92Val

c.275C>T · rs137960099 · VCV566199

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.9229	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -11.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 7.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 29 kb · p 0.53 · regional, not allelic
Overall
CADD	32.0	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00403% 65/1,613,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0064%	15,619
European (non-Finnish)	0.00331%	30,250
South Asian	0.0022%	45,539
African / African-American	0.00134%	74,892

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.Ala92Val
Coding: c.275C>T
MANE Select: NM_183235
dbSNP: rs137960099
Type: single nucleotide variant
Location: chr15:55228677 (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 92: the 'switch-ii' region

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.Ala92= 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-ala92val (accessed [today's date]).

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