Is DNAH8 p.Asp540Tyr (c.1618G>T) pathogenic?

DNAH8 p.Asp540Tyr (c.1618G>T) is classified Uncertain significance in DNAH8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: likely benign (0.2514); Ultra-rare (popmax 0.0312%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Asp540Tyr (c.1618G>T)?

DNAH8 p.Asp540Tyr (c.1618G>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Asp540Tyr (c.1618G>T) in the general population?

DNAH8 p.Asp540Tyr (c.1618G>T) is ultra-rare (popmax 0.0312%, amr) (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.Asp540Tyr (c.1618G>T)?

AlphaMissense predicts likely benign (score 0.2514) — an in-silico prediction, not a clinical call.

DNAH8 p.Asp540Tyr

c.1618G>T · rs1207266323 · VCV2057475

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2514 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.2514	likely benign
REVEL	0.27	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.39	acceptor gain · deltas
Pangolin	Δ0.50	gain · loss 0.36 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 131 kb · p 0.0001 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D323Y vs ClinVar D540Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% Admixed American · 16/51,228 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.00102% 16/1,566,662 alleles · ultra-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.Asp540Tyr
Coding: c.1618G>T
MANE Select: NM_001206927
dbSNP: rs1207266323
Type: single nucleotide variant
Location: chr6:38770413 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)

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-asp540tyr (accessed [today's date]).

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