Is DNAH8 p.Arg4336Lys (c.13007G>A) pathogenic?

DNAH8 p.Arg4336Lys (c.13007G>A) is classified Uncertain significance in DNAH8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.9416); Very rare (popmax 0.00306%, nfe); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Arg4336Lys (c.13007G>A)?

DNAH8 p.Arg4336Lys (c.13007G>A) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Arg4336Lys (c.13007G>A) in the general population?

DNAH8 p.Arg4336Lys (c.13007G>A) is very rare (popmax 0.00306%, 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 DNAH8 p.Arg4336Lys (c.13007G>A)?

AlphaMissense predicts likely pathogenic (score 0.9416) — an in-silico prediction, not a clinical call.

DNAH8 p.Arg4336Lys

c.13007G>A · rs372473768 · VCV1514681

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.9416	likely pathogenic
REVEL	0.334	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 112 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R4119K vs ClinVar R4336K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% European (non-Finnish) · 36/1,177,556 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00247% 36/1,459,130 alleles · very rare

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: DNAH8
Protein: p.Arg4336Lys
Coding: c.13007G>A
MANE Select: NM_001206927
dbSNP: rs372473768
Type: single nucleotide variant
Location: chr6:38984261 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 4336: a UniProt-annotated variant site (found in a patient with primary ciliary dyskinesia; uncertain significance)

Full DNAH8 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

DNAH8 c.10963-1G>A Likely pathogenic ★★ same condition
DNAH8 c.11563+1G>T Likely pathogenic ★★ same condition
DNAH8 c.2664+2T>C Likely pathogenic ★★ same condition
DNAH8 c.5734-1G>T Likely pathogenic ★★ same condition
DNAH8 p.Arg1090Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg2878Ter Pathogenic ★★ same condition
DNAH8 p.Arg4166Ter 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/dnah8-p-arg4336lys (accessed [today's date]).

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