Is DCAF8 p.Arg122Trp (c.364C>T) pathogenic?

DCAF8 p.Arg122Trp (c.364C>T) is classified Uncertain significance in DCAF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1408); Ultra-rare (popmax 0.0329%, mid); Associated with giant axonal neuropathy 2.

What condition is associated with DCAF8 p.Arg122Trp (c.364C>T)?

DCAF8 p.Arg122Trp (c.364C>T) is associated with giant axonal neuropathy 2 (ClinVar).

How common is DCAF8 p.Arg122Trp (c.364C>T) in the general population?

DCAF8 p.Arg122Trp (c.364C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about DCAF8 p.Arg122Trp (c.364C>T)?

AlphaMissense predicts likely benign (score 0.1408) — an in-silico prediction, not a clinical call.

DCAF8 p.Arg122Trp

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons inherited?

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

c.364C>T · rs768015097 · VCV2440710

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1408 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

giant axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.1408	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.39, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,009 bp · p 0.059 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00186% 30/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.00267%	37,470
European (non-Finnish)	0.00212%	47,202
South Asian	0.0011%	91,092

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: DCAF8
Protein: p.Arg122Trp
Coding: c.364C>T
MANE Select: NM_015726
dbSNP: rs768015097
Type: single nucleotide variant
Location: chr1:160240056 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 2 PDB
Residue 122: the 'disordered' region

Full DCAF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

giant axonal neuropathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

DCAF8 p.Arg122Gln Uncertain significance ★ ⚠ same residue
DCAF8 p.Arg122= Likely benign ★ same residue
DCAF8 p.Lys274= Benign/Likely benign ★★ same condition
DCAF8 p.Arg317Cys Likely pathogenic ★ same condition
DCAF8 p.Arg151Cys Uncertain significance ★ ⚠ same condition
DCAF8 p.Arg278His Uncertain significance ★ ⚠ same condition
DCAF8 p.Gly475Arg Uncertain significance ★ same condition
DCAF8 p.Ser576Phe 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/dcaf8-p-arg122trp (accessed [today's date]).

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