Is DKC1 p.Ala445Val (c.1334C>T) pathogenic?

DKC1 p.Ala445Val (c.1334C>T) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.0131%, amr); Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Ala445Val (c.1334C>T)?

DKC1 p.Ala445Val (c.1334C>T) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.Ala445Val (c.1334C>T) in the general population?

DKC1 p.Ala445Val (c.1334C>T) is ultra-rare (popmax 0.0131%, amr) (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.Ala445Val (c.1334C>T)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

DKC1 p.Ala445Val

c.1334C>T · rs782117503 · VCV858735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP 2.7
Regional constraint	o/e 0.84	unconstrained · MANE · 1,637 bp · p 0.19 · regional, not allelic
Overall
CADD	5.163	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 0.0131% Admixed American · 6/45,920 alleles

Filtering AF 0.00568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00157% 19/1,208,135 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0131%	7,653
South Asian	0.00352%	28,422
East Asian	0.00296%	33,787
Remaining individualsnot grpmax-eligible	0.00211%	47,479
European (non-Finnish)	0.00101%	99,280

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.Ala445Val
Coding: c.1334C>T
MANE Select: NM_001363
dbSNP: rs782117503
Type: single nucleotide variant
Location: chrX:154775269 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 445: the 'disordered' 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.Ala445= 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-ala445val (accessed [today's date]).

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