Is DKC1 p.Arg141Ser (c.421C>A) pathogenic?

DKC1 p.Arg141Ser (c.421C>A) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-09). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Arg141Ser (c.421C>A)?

DKC1 p.Arg141Ser (c.421C>A) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.Arg141Ser (c.421C>A) in the general population?

DKC1 p.Arg141Ser (c.421C>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.

What do computational predictors say about DKC1 p.Arg141Ser (c.421C>A)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

DKC1 p.Arg141Ser

c.421C>A · rs1486992777 · VCV2123933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 4% in DKC1
REVEL	0.64	indeterminate
SaProt	LLR -15.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.38	donor gain · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 4.2, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 4,035 bp · p 1.8e-12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Arg141Ser
Coding: c.421C>A
MANE Select: NM_001363
dbSNP: rs1486992777
Type: single nucleotide variant
Location: chrX:154766373 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 141: 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.Arg141Cys Uncertain significance ★★ ⚠ same residue
DKC1 p.Arg141= 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

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-arg141ser (accessed [today's date]).

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