Is DKC1 p.Arg250Cys (c.748C>T) pathogenic?

DKC1 p.Arg250Cys (c.748C>T) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.6887); Very rare (popmax 0.00218%, amr).

How common is DKC1 p.Arg250Cys (c.748C>T) in the general population?

DKC1 p.Arg250Cys (c.748C>T) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about DKC1 p.Arg250Cys (c.748C>T)?

AlphaMissense predicts likely pathogenic (score 0.6887) — an in-silico prediction, not a clinical call.

DKC1 p.Arg250Cys

c.748C>T · rs2523688444 · VCV1712649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6887	likely pathogenic
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -13.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Pangolin	Δ0.32	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 4, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 8,165 bp · p 2.1e-24 · regional, not allelic
Overall
CADD	29.0	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

Grpmax group 0.00218% Admixed American · 1/45,900 alleles

Overall 9.11e-05% 1/1,098,169 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.Arg250Cys
Coding: c.748C>T
MANE Select: NM_001363
dbSNP: rs2523688444
Type: single nucleotide variant
Location: chrX:154768409 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 250: a β-strand

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

Similar variants

DKC1 p.Arg250His 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
DKC1 c.16+5G>A 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-arg250cys (accessed [today's date]).

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