Is RAB23 p.Ile74= (c.222T>C) pathogenic?

RAB23 p.Ile74= (c.222T>C) is classified Likely benign in RAB23 (ClinVar, Single submitter, 3 submitters; last evaluated 2022-10-06). Very rare (popmax 0.00667%, amr); Associated with Carpenter syndrome.

What condition is associated with RAB23 p.Ile74= (c.222T>C)?

RAB23 p.Ile74= (c.222T>C) is associated with Carpenter syndrome, RAB23-related Carpenter syndrome (ClinVar).

How common is RAB23 p.Ile74= (c.222T>C) in the general population?

RAB23 p.Ile74= (c.222T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

RAB23 p.Ile74=

c.222T>C · rs759497648 · VCV989997

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Carpenter syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.7, phastCons 1
Overall
CADD	9.454	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,994 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000313% 5/1,599,956 alleles · very rare exomes 5/1,447,582 · genomes 0/152,374 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.00161%	62,056

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: RAB23
Protein: p.Ile74=
Coding: c.222T>C
MANE Select: NM_016277
dbSNP: rs759497648
Type: single nucleotide variant
Location: chr6:57207647 (GRCh38)
Gene constraint: LOEUF 0.838 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.39 · 6 PDB
Residue 74: an α-helix

Full RAB23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: RAB23-related Carpenter syndrome

Similar variants

RAB23 p.Arg28Ter Pathogenic/Likely pathogenic ★★ same condition
RAB23 p.Arg49Ter Pathogenic/Likely pathogenic ★★ same condition
RAB23 p.Arg80Ter Pathogenic/Likely pathogenic ★★ same condition
RAB23 p.Leu145Ter Pathogenic ★★ same condition
RAB23 c.481+4A>C Uncertain significance ★★ same condition
RAB23 p.Cys30Trp Uncertain significance ★★ ⚠ same condition
RAB23 p.Gly203Ser Uncertain significance ★★ ⚠ same condition
RAB23 p.Ser206Thr Uncertain significance ★★ ⚠ 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/rab23-p-ile74 (accessed [today's date]).

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