Is DRC4 p.Ala390Asp (c.1169C>A) pathogenic?

DRC4 p.Ala390Asp (c.1169C>A) is classified Uncertain significance in DRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2172); Very rare (popmax 0.00848%, nfe); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Ala390Asp (c.1169C>A)?

DRC4 p.Ala390Asp (c.1169C>A) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Ala390Asp (c.1169C>A) in the general population?

DRC4 p.Ala390Asp (c.1169C>A) is very rare (popmax 0.00848%, nfe) (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.Ala390Asp (c.1169C>A)?

AlphaMissense predicts likely benign (score 0.2172) — an in-silico prediction, not a clinical call.

DRC4 p.Ala390Asp

c.1169C>A · rs1452970741 · VCV1497204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.2172	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -9.06	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 2.6	phastCons 0.99
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	23.6	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 0.00848% European (non-Finnish) · 100/1,178,840 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00627% 101/1,610,388 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00848%	11,788
Remaining individualsnot grpmax-eligible	0.00161%	62,268

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.Ala390Asp
Coding: c.1169C>A
MANE Select: NM_001481
dbSNP: rs1452970741
Type: single nucleotide variant
Location: chr16:90040457 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 390: 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-ala390asp (accessed [today's date]).

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