Is DRC2 p.Arg294Cys (c.880C>T) pathogenic?

DRC2 p.Arg294Cys (c.880C>T) is classified Benign/Likely benign in DRC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1103); Common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with primary ciliary dyskinesia 27.

What condition is associated with DRC2 p.Arg294Cys (c.880C>T)?

DRC2 p.Arg294Cys (c.880C>T) is associated with primary ciliary dyskinesia 27 (ClinVar).

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 DRC2 p.Arg294Cys (c.880C>T)?

AlphaMissense predicts likely benign (score 0.1103) — an in-silico prediction, not a clinical call.

DRC2 p.Arg294Cys

Q: How common is DRC2 p.Arg294Cys (c.880C>T) in the general population?

DRC2 p.Arg294Cys (c.880C>T) is common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.880C>T · rs78877829 · VCV262221

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1103 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 27

Computational evidence

Protein change
AlphaMissense	0.1103	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 0.31, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 17 kb · p 0.19 · regional, not allelic
Overall
CADD	25.9	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 5.92% European (non-Finnish) · 69,844/1,179,950 alleles

Filtering AF 5.88% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.87%

Overall 5.13% 82,869/1,613,972 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	9.99%	10
European (non-Finnish)grpmax	5.92%	17
Amishnot grpmax-eligible	5.7%	18
Remaining individualsnot grpmax-eligible	4.45%	22
Admixed American	2.3%	43
Ashkenazi Jewishnot grpmax-eligible	1.96%	51
South Asian	1.2%	83
African / African-American	0.91%	110
Middle Eastern	0.562%	178
East Asian	0.0668%	1,496

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DRC2
Protein: p.Arg294Cys
Coding: c.880C>T
MANE Select: NM_033124
dbSNP: rs78877829
Type: single nucleotide variant
Location: chr12:48918757 (GRCh38)
Structure: AlphaFold pLDDT 83.21 · 1 PDB

Full DRC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 27 — 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

DRC2 p.Arg294His Uncertain significance ★★ ⚠ same residue
CCDC65 p.Arg70Gln Uncertain significance ★★ ⚠ same condition
CCDC65 p.Glu110Lys Uncertain significance ★★ ⚠ same condition
CCDC65 p.Lys158Asn Uncertain significance ★★ ⚠ same condition
DRC2 p.Ala109Val Uncertain significance ★★ ⚠ same condition
DRC2 p.Ala114Pro Uncertain significance ★★ ⚠ same condition
DRC2 p.Arg118Cys Uncertain significance ★★ ⚠ same condition
DRC2 p.Arg315Gln 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/drc2-p-arg294cys (accessed [today's date]).

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