Is DRC1 p.Arg375Cys (c.1123C>T) pathogenic?

DRC1 p.Arg375Cys (c.1123C>T) is classified Uncertain significance in DRC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-13). AlphaMissense: likely benign (0.1134); Ultra-rare (popmax 0.0165%, mid); Associated with primary ciliary dyskinesia.

What condition is associated with DRC1 p.Arg375Cys (c.1123C>T)?

DRC1 p.Arg375Cys (c.1123C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DRC1 p.Arg375Cys (c.1123C>T) in the general population?

DRC1 p.Arg375Cys (c.1123C>T) is ultra-rare (popmax 0.0165%, mid) (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 DRC1 p.Arg375Cys (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.1134) — an in-silico prediction, not a clinical call.

DRC1 p.Arg375Cys

c.1123C>T · rs145305515 · VCV998516

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.1134	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 0.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 55 kb · p 0.71 · regional, not allelic
Overall
CADD	24.4	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.0088% 142/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.0102%	9,834
East Asian	0.00891%	11,222
Admixed American	0.00833%	12,004
African / African-American	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0048%	20,835
South Asian	0.00439%	22,769

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: DRC1
Protein: p.Arg375Cys
Coding: c.1123C>T
MANE Select: NM_145038
dbSNP: rs145305515
Type: single nucleotide variant
Location: chr2:26444316 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.44 · 1 PDB
Residue 375: a UniProt-annotated variant site (in spgf80); a UniProt-annotated variant site (in cild21)

Full DRC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia — 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

DRC1 p.Arg375His Conflicting classifications of pathogenicity ★ ⚠ same residue
DRC1 p.Arg375Ser Uncertain significance ★ ⚠ same residue
DRC1 p.Gln118Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Gln337Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Ser642Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Ala250Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala391Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala416Gly 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/drc1-p-arg375cys (accessed [today's date]).

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