Is DRC4 p.His226= (c.678C>T) pathogenic?

DRC4 p.His226= (c.678C>T) is classified Likely benign in DRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0164%, mid); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.His226= (c.678C>T)?

DRC4 p.His226= (c.678C>T) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.His226= (c.678C>T) in the general population?

DRC4 p.His226= (c.678C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DRC4 p.His226=

c.678C>T · rs1008048501 · VCV1666230

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15
Overall
CADD	1.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00254% 41/1,613,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00331%	30,252
Admixed American	0.00167%	59,904

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: DRC4
Protein: p.His226=
Coding: c.678C>T
MANE Select: NM_001481
dbSNP: rs1008048501
Type: single nucleotide variant
Location: chr16:90036508 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 226: the 'microtubule-binding' region; a UniProt-annotated variant site (in cild33; loss of localization to cilia; abnormal cilia with axonemal disorganization)

Full DRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 33 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

DRC4 c.495+1G>T Likely pathogenic ★★ same condition
DRC4 p.Gln357Ter Pathogenic ★★ same condition
DRC4 p.Ala280Thr Uncertain significance ★★ ⚠ same condition
DRC4 p.Ala460Pro Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg143Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg164Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg203Gln Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg278Cys 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/drc4-p-his226 (accessed [today's date]).

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