Is DKC1 p.His259Pro (c.776A>C) pathogenic?

DKC1 p.His259Pro (c.776A>C) is classified Benign/Likely benign in DKC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.3173); Low-frequency (popmax 1.06%, afr); Associated with dyskeratosis congenita.

What condition is associated with DKC1 p.His259Pro (c.776A>C)?

DKC1 p.His259Pro (c.776A>C) is associated with dyskeratosis congenita (ClinVar).

How common is DKC1 p.His259Pro (c.776A>C) in the general population?

DKC1 p.His259Pro (c.776A>C) is low-frequency (popmax 1.06%, afr) (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.His259Pro (c.776A>C)?

AlphaMissense predicts likely benign (score 0.3173) — an in-silico prediction, not a clinical call.

DKC1 p.His259Pro

c.776A>C · rs61757608 · VCV377149

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3173 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.06%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.3173	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -8.05	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 11	GERP 4, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 8,165 bp · p 2.1e-24 · regional, not allelic
Overall
CADD	23.9	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 1.06% African / African-American · 605/56,986 alleles

Filtering AF 0.992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.964%

Overall 0.0547% 661/1,209,170 alleles · low-frequency exomes 338/1,097,913 · genomes 323/111,257 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.06%	94
Remaining individualsnot grpmax-eligible	0.0567%	1,763
Admixed American	0.0547%	1,827
South Asian	0.00176%	56,811
European (non-Finnish)	0.000335%	298,309

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.His259Pro
Coding: c.776A>C
MANE Select: NM_001363
dbSNP: rs61757608
Type: single nucleotide variant
Location: chrX:154769171 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 259: 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

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-his259pro (accessed [today's date]).

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