Is RAB27A p.Phe12Val (c.34T>G) pathogenic?

RAB27A p.Phe12Val (c.34T>G) is classified Uncertain significance in RAB27A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.5221); Absent from gnomAD v4.1; Associated with Griscelli syndrome type 2.

What condition is associated with RAB27A p.Phe12Val (c.34T>G)?

RAB27A p.Phe12Val (c.34T>G) is associated with Griscelli syndrome type 2 (ClinVar).

How common is RAB27A p.Phe12Val (c.34T>G) in the general population?

RAB27A p.Phe12Val (c.34T>G) is absent from gnomAD v4.1 (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.Phe12Val (c.34T>G)?

AlphaMissense predicts ambiguous (score 0.5221) — an in-silico prediction, not a clinical call.

RAB27A p.Phe12Val

c.34T>G · VCV4714993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5221 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Griscelli syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.5221	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -3.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 7.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 29 kb · p 0.53 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAB27A
Protein: p.Phe12Val
Coding: c.34T>G
MANE Select: NM_183235
Type: single nucleotide variant
Location: chr15:55234901 (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 12: a β-strand

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.Phe12Ser 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
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-phe12val (accessed [today's date]).

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