Is DNAH5 p.Arg4084Leu (c.12251G>T) pathogenic?

DNAH5 p.Arg4084Leu (c.12251G>T) is classified Uncertain significance in DNAH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.7657); Absent from gnomAD v4.1; Associated with primary ciliary dyskinesia.

What condition is associated with DNAH5 p.Arg4084Leu (c.12251G>T)?

DNAH5 p.Arg4084Leu (c.12251G>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH5 p.Arg4084Leu (c.12251G>T) in the general population?

DNAH5 p.Arg4084Leu (c.12251G>T) is absent from gnomAD v4.1 (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 DNAH5 p.Arg4084Leu (c.12251G>T)?

AlphaMissense predicts likely pathogenic (score 0.7657) — an in-silico prediction, not a clinical call.

DNAH5 p.Arg4084Leu

c.12251G>T · rs140832239 · VCV2238336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7657 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.7657	likely pathogenic
REVEL	0.273	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 228 kb · p 0.16 · regional, not allelic
Overall
CADD	22.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNAH5
Protein: p.Arg4084Leu
Coding: c.12251G>T
MANE Select: NM_001369
dbSNP: rs140832239
Type: single nucleotide variant
Location: chr5:13721028 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4084: the 'aaa 6' region

Full DNAH5 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

DNAH5 p.Arg4084Gln Conflicting classifications of pathogenicity ★ same residue
DNAH5 p.Arg4084Trp Conflicting classifications of pathogenicity ★ same residue
DNAH5 c.10555+1G>C Likely pathogenic ★★ same condition
DNAH5 c.1089+1G>A Pathogenic ★★ same condition
DNAH5 c.11028+2T>C Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.11029-2A>T Pathogenic/Likely pathogenic ★★ same condition
DNAH5 c.11571-1G>A Pathogenic ★★ same condition
DNAH5 c.12910-1G>C Pathogenic/Likely pathogenic ★★ 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/dnah5-p-arg4084leu (accessed [today's date]).

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