Is DKC1 p.Arg449Gln (c.1346G>A) pathogenic?

DKC1 p.Arg449Gln (c.1346G>A) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely benign (0.163); Very rare (popmax 0.00174%, afr); Associated with Inherited Immunodeficiency Diseases.

What condition is associated with DKC1 p.Arg449Gln (c.1346G>A)?

DKC1 p.Arg449Gln (c.1346G>A) is associated with Inherited Immunodeficiency Diseases (ClinVar).

How common is DKC1 p.Arg449Gln (c.1346G>A) in the general population?

DKC1 p.Arg449Gln (c.1346G>A) is very rare (popmax 0.00174%, afr) (gnomAD).

What do computational predictors say about DKC1 p.Arg449Gln (c.1346G>A)?

AlphaMissense predicts likely benign (score 0.163) — an in-silico prediction, not a clinical call.

DKC1 p.Arg449Gln

c.1346G>A · rs1289430524 · VCV827703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inherited Immunodeficiency Diseases

Computational evidence

Protein change
AlphaMissense	0.163	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -7.13	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 7	GERP 4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,637 bp · p 0.19 · regional, not allelic
Overall
CADD	25.7	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 0.00174% African / African-American · 1/57,321 alleles

Overall 0.000165% 2/1,210,369 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00174%	57,321
European (non-Finnish)	0.000112%	895,167

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.Arg449Gln
Coding: c.1346G>A
MANE Select: NM_001363
dbSNP: rs1289430524
Type: single nucleotide variant
Location: chrX:154776194 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 449: the 'disordered' region; the 'nuclear and nucleolar localization' region

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

Disease context

Inherited Immunodeficiency Diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DKC1 p.Arg449Gly Pathogenic ★ ⚠ same residue
DKC1 p.Arg449Pro Uncertain significance ★ same residue
DKC1 p.Ala353Val Pathogenic ★★ ⚠ same type
DKC1 p.Asn63Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
DKC1 p.Ile38Met Likely pathogenic ★★ ⚠ same type
DKC1 p.Thr49Met Pathogenic ★★ ⚠ same type
DKC1 p.Thr66Ala Pathogenic/Likely pathogenic ★★ ⚠ same type
DKC1 c.1339-10T>G Uncertain significance ★★ same type

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-arg449gln (accessed [today's date]).

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