Is DKC1 p.Pro404Ala (c.1210C>G) pathogenic?

DKC1 p.Pro404Ala (c.1210C>G) is classified Uncertain significance in DKC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-30). AlphaMissense: likely benign (0.0579); Very rare (popmax 0.000112%, nfe); Associated with DKC1-related disorder.

What condition is associated with DKC1 p.Pro404Ala (c.1210C>G)?

DKC1 p.Pro404Ala (c.1210C>G) is associated with DKC1-related disorder, dyskeratosis congenita (ClinVar).

How common is DKC1 p.Pro404Ala (c.1210C>G) in the general population?

DKC1 p.Pro404Ala (c.1210C>G) is very rare (popmax 0.000112%, 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.Pro404Ala (c.1210C>G)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

DKC1 p.Pro404Ala

c.1210C>G · rs1347625639 · VCV967191

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DKC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -11.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.73, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 8,165 bp · p 2.1e-24 · regional, not allelic
Overall
CADD	12.92	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 0.000112% European (non-Finnish) · 1/895,082 alleles

Overall 8.26e-05% 1/1,210,110 alleles · very rare exomes 0/1,097,941 · genomes 1/112,169 · joint denominator

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.Pro404Ala
Coding: c.1210C>G
MANE Select: NM_001363
dbSNP: rs1347625639
Type: single nucleotide variant
Location: chrX:154774656 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 404: a β-strand

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

Disease context

Also linked: dyskeratosis congenita

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-pro404ala (accessed [today's date]).

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