Is DRC4 p.Leu345Arg (c.1034T>G) pathogenic?

DRC4 p.Leu345Arg (c.1034T>G) is classified Uncertain significance in DRC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-19). AlphaMissense: ambiguous (0.3443); Very rare (popmax 0.0035%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DRC4 p.Leu345Arg (c.1034T>G)?

DRC4 p.Leu345Arg (c.1034T>G) is associated with Inborn genetic diseases, primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Leu345Arg (c.1034T>G) in the general population?

DRC4 p.Leu345Arg (c.1034T>G) is very rare (popmax 0.0035%, nfe) (gnomAD).

What do computational predictors say about DRC4 p.Leu345Arg (c.1034T>G)?

AlphaMissense predicts ambiguous (score 0.3443) — an in-silico prediction, not a clinical call.

DRC4 p.Leu345Arg

c.1034T>G · rs372636476 · VCV2182469

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3443	ambiguous
REVEL	0.653	pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	24.3	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 0.0035% European (non-Finnish) · 41/1,171,184 alleles

Filtering AF 0.0026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00234%

Overall 0.00276% 44/1,595,034 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00486%	20,589
European (non-Finnish)grpmax	0.0035%	28,565

Remaining individuals 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: DRC4
Protein: p.Leu345Arg
Coding: c.1034T>G
MANE Select: NM_001481
dbSNP: rs372636476
Type: single nucleotide variant
Location: chr16:90040322 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 345: a UniProt-annotated variant site (in cild33; loss of localization to cilia; abnormal cilia with axonemal disorganization)

Full DRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary ciliary dyskinesia 33

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-leu345arg (accessed [today's date]).

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