Is DNAH8 p.Pro1284Leu (c.3851C>T) pathogenic?

DNAH8 p.Pro1284Leu (c.3851C>T) is classified Uncertain significance in DNAH8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-14). AlphaMissense: ambiguous (0.4863); Ultra-rare (popmax 0.0337%, mid); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Pro1284Leu (c.3851C>T)?

DNAH8 p.Pro1284Leu (c.3851C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Pro1284Leu (c.3851C>T) in the general population?

DNAH8 p.Pro1284Leu (c.3851C>T) is ultra-rare (popmax 0.0337%, 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 DNAH8 p.Pro1284Leu (c.3851C>T)?

AlphaMissense predicts ambiguous (score 0.4863) — an in-silico prediction, not a clinical call.

DNAH8 p.Pro1284Leu

c.3851C>T · rs562900966 · VCV964004

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, mid)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.4863	ambiguous
REVEL	0.212	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.86 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 131 kb · p 0.0001 · regional, not allelic
Overall
CADD	21.8	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 P1067L vs ClinVar P1284L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0337% Middle Eastern · 2/5,940 alleles

Filtering AF 0.00593% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00649% 103/1,586,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0661%	1,514
Middle Easterngrpmax	0.0337%	2,970
South Asian	0.0104%	9,615
East Asian	0.00673%	14,857
European (non-Finnish)	0.00369%	27,094
Admixed American	0.00356%	28,108
Remaining individualsnot grpmax-eligible	0.00325%	30,732

Finnish 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: DNAH8
Protein: p.Pro1284Leu
Coding: c.3851C>T
MANE Select: NM_001206927
dbSNP: rs562900966
Type: single nucleotide variant
Location: chr6:38826159 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 1284: 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 p.Pro1284= Likely benign ★ same residue
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

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-pro1284leu (accessed [today's date]).

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