Is DKC1 p.Arg322Gln (c.965G>A) pathogenic?

DKC1 p.Arg322Gln (c.965G>A) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 3 submitters; last evaluated 2021-09-02). AlphaMissense: ambiguous (0.4756); Very rare (popmax 0.00175%, sas); Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.Arg322Gln (c.965G>A)?

DKC1 p.Arg322Gln (c.965G>A) is associated with dyskeratosis congenita, dyskeratosis congenita, X-linked (ClinVar).

How common is DKC1 p.Arg322Gln (c.965G>A) in the general population?

DKC1 p.Arg322Gln (c.965G>A) is very rare (popmax 0.00175%, sas) (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.Arg322Gln (c.965G>A)?

AlphaMissense predicts ambiguous (score 0.4756) — an in-silico prediction, not a clinical call.

DKC1 p.Arg322Gln

c.965G>A · rs121912291 · VCV38959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.4756	ambiguous
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -13.52	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	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	28.2	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 0.00175% South Asian · 1/57,000 alleles

Overall 0.000182% 2/1,097,526 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,642
South Asiangrpmax	0.00175%	57,000

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg322Gln
Coding: c.965G>A
MANE Select: NM_001363
dbSNP: rs121912291
Type: single nucleotide variant
Location: chrX:154770808 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 322: the pua domain; a UniProt-annotated variant site (in dkcx); a β-strand

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

Also linked: dyskeratosis congenita, X-linked

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.Arg322Ter Likely pathogenic ★ same residue
DKC1 p.Ala353Val Pathogenic ★★ ⚠ same condition
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

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-arg322gln (accessed [today's date]).

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