Is DRC4 p.Arg404His (c.1211G>A) pathogenic?

DRC4 p.Arg404His (c.1211G>A) is classified Conflicting classifications of pathogenicity in DRC4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0653); Rare (popmax 0.247%, amr); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Arg404His (c.1211G>A)?

DRC4 p.Arg404His (c.1211G>A) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Arg404His (c.1211G>A) in the general population?

DRC4 p.Arg404His (c.1211G>A) is rare (popmax 0.247%, amr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

What do computational predictors say about DRC4 p.Arg404His (c.1211G>A)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

DRC4 p.Arg404His

c.1211G>A · rs755682241 · VCV707684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.37	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 1.7	phastCons 0.94
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.1	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 0.247% Admixed American · 144/58,220 alleles

Filtering AF 0.214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.202%

Overall 0.0104% 166/1,598,824 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.247%	404
Remaining individualsnot grpmax-eligible	0.00647%	15,461
South Asian	0.00451%	22,169
East Asian	0.00227%	44,048
African / African-American	0.00134%	74,534
European (non-Finnish)	0.00102%	97,823

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.Arg404His
Coding: c.1211G>A
MANE Select: NM_001481
dbSNP: rs755682241
Type: single nucleotide variant
Location: chr16:90040499 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 404: a UniProt-annotated variant site (in cild33; loss of localization to cilia; abnormal cilia with axonemal disorganization); the 'interaction with smo' region

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 p.Arg404Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
DRC4 p.Arg404Gly Uncertain significance ★ ⚠ same residue
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

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-arg404his (accessed [today's date]).

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