Is DNAH8 p.Phe3591Leu (c.10773C>G) pathogenic?

DNAH8 p.Phe3591Leu (c.10773C>G) is classified Conflicting classifications of pathogenicity in DNAH8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9566); Rare (popmax 0.13%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Phe3591Leu (c.10773C>G)?

DNAH8 p.Phe3591Leu (c.10773C>G) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Phe3591Leu (c.10773C>G) in the general population?

DNAH8 p.Phe3591Leu (c.10773C>G) is rare (popmax 0.13%, 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.Phe3591Leu (c.10773C>G)?

AlphaMissense predicts likely pathogenic (score 0.9566) — an in-silico prediction, not a clinical call.

DNAH8 p.Phe3591Leu

c.10773C>G · rs147574550 · VCV454538

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9566 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, amr)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.9566	likely pathogenic
REVEL	0.536	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP -0.88, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 112 kb · p 0.0022 · regional, not allelic
Overall
CADD	18.94	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 F3374L vs ClinVar F3591L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.13% Admixed American · 78/59,952 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0982%

Overall 0.0448% 723/1,613,450 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.13%	769
European (non-Finnish)	0.0514%	1,947
Remaining individualsnot grpmax-eligible	0.0496%	2,015
African / African-American	0.0107%	9,360

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.Phe3591Leu
Coding: c.10773C>G
MANE Select: NM_001206927
dbSNP: rs147574550
Type: single nucleotide variant
Location: chr6:38923168 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 3591: a UniProt-annotated variant site (found in a patient with primary ciliary dyskinesia; uncertain significance); the 'aaa 5' region

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-phe3591leu (accessed [today's date]).

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