Is DCAF8 p.Lys274= (c.822G>A) pathogenic?

DCAF8 p.Lys274= (c.822G>A) is classified Benign/Likely benign in DCAF8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-02-14). Low-frequency (popmax 4.78%, afr); Associated with giant axonal neuropathy 2.

What condition is associated with DCAF8 p.Lys274= (c.822G>A)?

DCAF8 p.Lys274= (c.822G>A) is associated with giant axonal neuropathy 2 (ClinVar).

How common is DCAF8 p.Lys274= (c.822G>A) in the general population?

DCAF8 p.Lys274= (c.822G>A) is low-frequency (popmax 4.78%, afr) (gnomAD).

DCAF8 p.Lys274=

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.822G>A · rs2275702 · VCV788287

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.78%, afr)

Conditions

giant axonal neuropathy 2

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 3.9	GERP 2.8, phastCons 1
Overall
CADD	13.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.78% African / African-American · 3,585/74,996 alleles

Filtering AF 4.65% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.6%

Overall 0.435% 7,020/1,613,470 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.78%	21
East Asian	3.83%	26
Admixed American	1.89%	53
Remaining individualsnot grpmax-eligible	0.501%	200
Middle Eastern	0.463%	216
South Asian	0.077%	1,299
European (non-Finnish)	0.0151%	6,628

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.Lys274=
Coding: c.822G>A
MANE Select: NM_015726
dbSNP: rs2275702
Type: single nucleotide variant
Location: chr1:160238649 (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.Arg122Trp Uncertain significance ★★ ⚠ 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
DCAF8 p.Ser130del Uncertain significance ★ same condition
DCAF8 p.Arg117Cys Uncertain significance ★★ ⚠ same type

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-lys274 (accessed [today's date]).

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