Is DKC1 p.Ile466Val (c.1396A>G) pathogenic?

DKC1 p.Ile466Val (c.1396A>G) is classified Uncertain significance in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.0646); Very rare (popmax 0.000112%, nfe); Associated with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1.

How common is DKC1 p.Ile466Val (c.1396A>G) in the general population?

DKC1 p.Ile466Val (c.1396A>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about DKC1 p.Ile466Val (c.1396A>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

DKC1 p.Ile466Val

Q: What condition is associated with DKC1 p.Ile466Val (c.1396A>G)?

DKC1 p.Ile466Val (c.1396A>G) is associated with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1, dyskeratosis congenita, X-linked (ClinVar).

c.1396A>G · VCV3598200

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -3.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -6
Regional constraint	o/e 0.84	unconstrained · MANE · 1,637 bp · p 0.19 · regional, not allelic
Overall
CADD	0.102	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 0.000112% European (non-Finnish) · 1/895,395 alleles

Overall 9.11e-05% 1/1,097,922 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.Ile466Val
Coding: c.1396A>G
MANE Select: NM_001363
Type: single nucleotide variant
Location: chrX:154776244 (GRCh38)
Structure: AlphaFold pLDDT 79.74 · 7 PDB
Residue 466: 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

cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, X-linked

Similar variants

DKC1 p.Ile466Asn Uncertain significance ★ ⚠ same residue
DKC1 p.Ile466Met Uncertain significance ★ ⚠ same residue
DKC1 p.Ala353Val 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 p.Gln414Glu Uncertain significance ★★ ⚠ same condition
DKC1 p.Glu440Lys 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-ile466val (accessed [today's date]).

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