Is DKC1 p.Glu25Asp (c.75A>T) pathogenic?

DKC1 p.Glu25Asp (c.75A>T) is classified Uncertain significance in DKC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00176%, sas); Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Glu25Asp (c.75A>T)?

DKC1 p.Glu25Asp (c.75A>T) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.Glu25Asp (c.75A>T) in the general population?

DKC1 p.Glu25Asp (c.75A>T) is very rare (popmax 0.00176%, sas) (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.Glu25Asp (c.75A>T)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

DKC1 p.Glu25Asp

c.75A>T · rs2148509198 · VCV1721936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP 1.3, phastCons 0.002
Regional constraint	o/e 0.35	constrained · MANE · 4,035 bp · p 1.8e-12 · regional, not allelic
Overall
CADD	7.723	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,818 alleles

Overall 9.18e-05% 1/1,089,243 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.Glu25Asp
Coding: c.75A>T
MANE Select: NM_001363
dbSNP: rs2148509198
Type: single nucleotide variant
Location: chrX:154764957 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 25: an α-helix

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.Glu25= Likely benign ★ same residue
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

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-glu25asp (accessed [today's date]).

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