Is DCAF8 p.Arg151Cys (c.451C>T) pathogenic?

DCAF8 p.Arg151Cys (c.451C>T) is classified Uncertain significance in DCAF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-03). AlphaMissense: likely benign (0.1119); Very rare (popmax 0.00127%, nfe); Associated with giant axonal neuropathy 2.

What condition is associated with DCAF8 p.Arg151Cys (c.451C>T)?

DCAF8 p.Arg151Cys (c.451C>T) is associated with giant axonal neuropathy 2 (ClinVar).

How common is DCAF8 p.Arg151Cys (c.451C>T) in the general population?

DCAF8 p.Arg151Cys (c.451C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about DCAF8 p.Arg151Cys (c.451C>T)?

AlphaMissense predicts likely benign (score 0.1119) — an in-silico prediction, not a clinical call.

DCAF8 p.Arg151Cys

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.451C>T · rs1228444617 · VCV930290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

giant axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.1119	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 15 kb · p 9.7e-17 · regional, not allelic
Overall
CADD	32.0	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 0.00127% European (non-Finnish) · 15/1,180,030 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,614,222 alleles · very rare exomes 16/1,461,880 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00127%	78,669
South Asian	0.0011%	91,086

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.Arg151Cys
Coding: c.451C>T
MANE Select: NM_015726
dbSNP: rs1228444617
Type: single nucleotide variant
Location: chr1:160239969 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 2 PDB

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.Arg151Leu Uncertain significance ★ ⚠ same residue
DCAF8 p.Arg122Trp Uncertain significance ★★ ⚠ same condition
DCAF8 p.Lys274= Benign/Likely benign ★★ same condition
DCAF8 p.Arg317Cys Likely pathogenic ★ ⚠ same condition
DCAF8 p.Arg278His Uncertain significance ★ ⚠ same condition
DCAF8 p.Gly475Arg Uncertain significance ★ ⚠ same condition
DCAF8 p.Ser576Phe Uncertain significance ★ ⚠ same condition
DCAF8 p.Ser130del 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-arg151cys (accessed [today's date]).

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