Is DKC1 p.Glu488Lys (c.1462G>A) pathogenic?

DKC1 p.Glu488Lys (c.1462G>A) is classified Conflicting classifications of pathogenicity in DKC1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-11). AlphaMissense: likely benign (0.1074); Very rare (popmax 0.000226%, nfe); Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Glu488Lys (c.1462G>A)?

DKC1 p.Glu488Lys (c.1462G>A) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.Glu488Lys (c.1462G>A) in the general population?

DKC1 p.Glu488Lys (c.1462G>A) is very rare (popmax 0.000226%, nfe) (gnomAD).

How is Dyskeratosis congenita inherited?

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

What do computational predictors say about DKC1 p.Glu488Lys (c.1462G>A)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

DKC1 p.Glu488Lys

c.1462G>A · rs782486294 · VCV2699570

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000226%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP 3, phastCons 0.46
Regional constraint	o/e 0.84	unconstrained · MANE · 1,637 bp · p 0.19 · regional, not allelic
Overall
CADD	12.21	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 0.000226% European (non-Finnish) · 2/886,390 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000185% 2/1,080,804 alleles · very rare

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: DKC1
Protein: p.Glu488Lys
Coding: c.1462G>A
MANE Select: NM_001363
dbSNP: rs782486294
Type: single nucleotide variant
Location: chrX:154776310 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 488: the 'disordered' region; the 'nuclear and nucleolar localization' region

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-glu488lys (accessed [today's date]).

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