Is DNAH5 p.Arg4084Trp (c.12250C>T) pathogenic?

DNAH5 p.Arg4084Trp (c.12250C>T) is classified Conflicting classifications of pathogenicity in DNAH5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.6326); Ultra-rare (popmax 0.0164%, mid); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH5 p.Arg4084Trp (c.12250C>T)?

DNAH5 p.Arg4084Trp (c.12250C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH5 p.Arg4084Trp (c.12250C>T) in the general population?

DNAH5 p.Arg4084Trp (c.12250C>T) is ultra-rare (popmax 0.0164%, 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 DNAH5 p.Arg4084Trp (c.12250C>T)?

AlphaMissense predicts likely pathogenic (score 0.6326) — an in-silico prediction, not a clinical call.

DNAH5 p.Arg4084Trp

c.12250C>T · rs752895938 · VCV1017090

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.6326	likely pathogenic
REVEL	0.324	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 228 kb · p 0.16 · regional, not allelic
Overall
CADD	25.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00105% 17/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.005%	19,997
African / African-American	0.00267%	37,446
East Asian	0.00223%	44,884
South Asian	0.0011%	91,076
European (non-Finnish)	0.000763%	131,110

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: DNAH5
Protein: p.Arg4084Trp
Coding: c.12250C>T
MANE Select: NM_001369
dbSNP: rs752895938
Type: single nucleotide variant
Location: chr5:13721029 (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.Arg4084Leu Uncertain significance ★ ⚠ 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-arg4084trp (accessed [today's date]).

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