Is DKC1 p.Ala222= (c.666T>A) pathogenic?

DKC1 p.Ala222= (c.666T>A) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-13). Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Ala222= (c.666T>A)?

DKC1 p.Ala222= (c.666T>A) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.Ala222= (c.666T>A) in the general population?

DKC1 p.Ala222= (c.666T>A) is absent from gnomAD v4.1 (gnomAD).

How is Dyskeratosis congenita inherited?

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

DKC1 p.Ala222=

c.666T>A · VCV3730500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

dyskeratosis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.089	moderately benign-leaning
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.20	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -6.4	GERP -8.2
Overall
CADD	0.733	PHRED · no single calibrated threshold — expert panels disagree

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: DKC1
Protein: p.Ala222=
Coding: c.666T>A
MANE Select: NM_001363
Type: single nucleotide variant
Location: chrX:154768327 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB

Full DKC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyskeratosis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

DKC1 p.Ala353Val Pathogenic ★★ ⚠ same condition
DKC1 p.Asn63Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
DKC1 p.Thr49Met Pathogenic ★★ ⚠ same condition
DKC1 p.Thr66Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
DKC1 c.1339-10T>G Uncertain significance ★★ same condition
DKC1 c.16+5G>A Uncertain significance ★★ same condition
DKC1 c.640+3G>A Uncertain significance ★★ same condition
DKC1 p.Ala162Thr 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/dkc1-p-ala222 (accessed [today's date]).

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