Is DCT p.His223Arg (c.668A>G) pathogenic?

DCT p.His223Arg (c.668A>G) is classified Uncertain significance in DCT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.8016); Very rare (popmax 0.00331%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DCT p.His223Arg (c.668A>G)?

DCT p.His223Arg (c.668A>G) is associated with Inborn genetic diseases (ClinVar).

How common is DCT p.His223Arg (c.668A>G) in the general population?

DCT p.His223Arg (c.668A>G) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about DCT p.His223Arg (c.668A>G)?

AlphaMissense predicts likely pathogenic (score 0.8016) — an in-silico prediction, not a clinical call.

DCT p.His223Arg

c.668A>G · rs377490914 · VCV3080639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8016 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8016	likely pathogenic
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -11.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 39 kb · p 0.21 · regional, not allelic
Overall
CADD	27.0	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 0.00331% European (non-Finnish) · 39/1,178,598 alleles

Filtering AF 0.00248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00254% 41/1,611,324 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00331%	30,220
Remaining individualsnot grpmax-eligible	0.0016%	62,320
African / African-American	0.00134%	74,886

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: DCT
Protein: p.His223Arg
Coding: c.668A>G
MANE Select: NM_001922
dbSNP: rs377490914
Type: single nucleotide variant
Location: chr13:94466586 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.33 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DCT c.1180-2098C>T Uncertain significance ★ same condition
DCT c.1180-2111A>G Uncertain significance ★ same condition
DCT p.Ala144Thr Uncertain significance ★ ⚠ same condition
DCT p.Ala206Thr Uncertain significance ★ ⚠ same condition
DCT p.Ala357Glu Uncertain significance ★ ⚠ same condition
DCT p.Ala381Thr Uncertain significance ★ ⚠ same condition
DCT p.Ala386Thr Uncertain significance ★ ⚠ same condition
DCT p.Arg202Cys 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/dct-p-his223arg (accessed [today's date]).

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