Is DKC1 p.Ala353Val (c.1058C>T) pathogenic?

DKC1 p.Ala353Val (c.1058C>T) is classified Pathogenic in DKC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-05-04). AlphaMissense: ambiguous (0.467); Very rare (popmax 0.000226%, nfe); Associated with DKC1-Related Disorders.

What condition is associated with DKC1 p.Ala353Val (c.1058C>T)?

DKC1 p.Ala353Val (c.1058C>T) is associated with DKC1-Related Disorders, dyskeratosis congenita, X-linked, dyskeratosis congenita (ClinVar).

How common is DKC1 p.Ala353Val (c.1058C>T) in the general population?

DKC1 p.Ala353Val (c.1058C>T) is very rare (popmax 0.000226%, nfe) (gnomAD).

What do computational predictors say about DKC1 p.Ala353Val (c.1058C>T)?

AlphaMissense predicts ambiguous (score 0.467) — an in-silico prediction, not a clinical call.

DKC1 p.Ala353Val

c.1058C>T · rs121912288 · VCV11587

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000226%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DKC1-Related Disorders

Computational evidence

Protein change
AlphaMissense	0.467	ambiguous
REVEL	0.739	pathogenic-leaning
SaProt	LLR -9.28	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.2, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 8,165 bp · p 2.1e-24 · regional, not allelic
Overall
CADD	23.6	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) · 2/883,945 alleles

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

Overall 0.000184% 2/1,085,387 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.Ala353Val
Coding: c.1058C>T
MANE Select: NM_001363
dbSNP: rs121912288
Type: single nucleotide variant
Location: chrX:154773152 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 353: an α-helix; the pua domain; a UniProt-annotated variant site (in dkcx and hhs; increases interaction with shq1)

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

Disease context

Also linked: dyskeratosis congenita, X-linked dyskeratosis congenita

Similar variants

DKC1 p.Ala353= Likely benign ★★ same residue
DKC1 p.Asn63Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
DKC1 p.Ile38Met 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-ala353val (accessed [today's date]).

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