Is DRC4 p.Ser375= (c.1125C>T) pathogenic?

DRC4 p.Ser375= (c.1125C>T) is classified Likely benign in DRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-22). Rare (popmax 0.102%, mid); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Ser375= (c.1125C>T)?

DRC4 p.Ser375= (c.1125C>T) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Ser375= (c.1125C>T) in the general population?

DRC4 p.Ser375= (c.1125C>T) is rare (popmax 0.102%, 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.Ser375=

c.1125C>T · rs374475661 · VCV766988

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.102%, 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 -11
Overall
CADD	0.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.102% Middle Eastern · 6/5,910 alleles

Filtering AF 0.0442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0301%

Overall 0.00738% 119/1,612,208 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.102%	985
South Asian	0.0154%	6,474
Remaining individualsnot grpmax-eligible	0.00801%	12,479
African / African-American	0.008%	12,499
European (non-Finnish)	0.00704%	14,208
Admixed American	0.00501%	19,959
East Asian	0.00446%	22,411

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.Ser375=
Coding: c.1125C>T
MANE Select: NM_001481
dbSNP: rs374475661
Type: single nucleotide variant
Location: chr16:90040413 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 375: 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 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-ser375 (accessed [today's date]).

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